{"PMID":31523393,"Year":2019,"Title":"Tumor penetrating nanomedicine targeting both an oncomiR and an oncogene in pancreatic cancer.","Abstract":"Developing new targeted therapy for pancreatic cancer is one of the major current challenges in cancer research. KRAS mutations and miRNA dysregulation (e.g. miR-21-5p oncomiR) play key roles in Pancreatic Ductal Adenocarcinoma (PDAC), leading to rapid progression of the disease. As the KRAS mutation is a main driver of PDAC, anti-KRAS strategies remain a major therapeutic approach for PDAC treatment. Previously, utilization of either siKRAS or small chemically modified single-stranded RNA molecules that specifically disable miR-21 (anti-miR-21) were effective in slowing PDAC tumor growth in various tumor models when packaged in an innovative delivery system (TPN) required for efficient drug delivery to the PDAC tumor site. Here we have tested the utility of targeting the KRAS pathway through multiple mechanisms and via dual targeting of a PDAC oncomiR and oncogene. Initially we found that miR-217, which has been shown to directly regulate KRAS expression, is downregulated in our PDAC samples, thus we tested the benefits of anti-miR-21, miR-217 mimic or siKRAS loaded into the tumor-penetrating nanoparticles (TPN) that we had previously shown to potently target the largely impenetrable PDAC tumors, and found an enhanced anti-tumoral response upon dual treatments in KRAS-mutated PDAC models.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":31467274,"Year":2019,"Title":"Distinct methylation levels of mature microRNAs in gastrointestinal cancers.","Abstract":"The biological significance of micro (mi)RNAs has traditionally been evaluated according to their RNA expression levels based on the assumption that miRNAs recognize and regulate their targets in an unvarying fashion. Here we show that a fraction of mature miRNAs including miR-17-5p, -21-5p, and -200c-3p and let-7a-5p harbor methyl marks that potentially alter their stability and target recognition. Importantly, methylation of these miRNAs was significantly increased in cancer tissues as compared to paired normal tissues. Furthermore, miR-17-5p methylation level in serum samples distinguished early pancreatic cancer patients from healthy controls with extremely high sensitivity and specificity. These findings provide a basis for diagnostic strategies for early-stage cancer and add a dimension to our understanding of miRNA biology.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":31413212,"Year":2019,"Title":"[MicroRNA-21 correlates TGF-beta1 pathway of pancreatic ductal adenocarcinoma].","Abstract":"OBJECTIVE: To conduct genetic analysis of pancreatic ductal adenocarcinoma tissues and analyze the correlation between targeted microRNA (miRNA) and pathways in pancreatic ductal adenocarcinoma. Methods: We collected 19 samples of peripheral venous blood serum from patients with pancreatic ductal adenocarcinoma in Hainan Provincial Hospital of Chinese Medicine, and also collected 21 blood serum samples as a control group of non-pancreatic ductal adenocarcinoma. We used the bioinformatics analysis of literature GCBI data platform for screening and analyzing the genetics of pancreatic ductal adenocarcinoma samples. Through GCBI data platform of hierarchy clustering analysis and the enrichment of gene function analysis, the relevant miRNA was screened as a research object in patients with pancreatic ductal adenocarcinoma. The miRNA was screened by literature analysis and pancreatic cancer gene analysis. Real-time PCR and Western blotting were carried out to study the relationship between the selected miRNA and TGF-beta1 by overexpression and suppression of the gene in pancreatic ductal adenocarcinoma cells. Results: MiRNA-21 was screened as a gene associated with pancreatic ductal carcinoma via hierarchy clustering analysis and gene function analysis. MiRNA-21 was highly expressed in the pancreatic ductal carcinoma patients. Expressions of TGF-beta1 were inhibired in miRNA-21 overexpressed PANC-1. While the expression of miRNA-21 was inhibited, TGF-beta1 expression increased obviously. Conclusion: MiRNA-21 is highly expressed in patients with pancreatic ductal adenocarcinoma, can regulate the expression of TGF-beta1, which may be a mechanism of miRNA-21 in pancreatic ductal adenocarcinoma.","Language":"chi","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":31311829,"Year":2019,"Title":"Identification of novel genes associated with a poor prognosis in pancreatic ductal adenocarcinoma via a bioinformatics analysis.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a class of the commonest malignant carcinomas. The present study aimed to elucidate the potential biomarker and prognostic targets in PDAC. The array data of GSE41368, GSE43795, GSE55643, and GSE41369 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) and differentially expressed microRNAs (DEmiRNAs) in PDAC were obtained by using GEO2R, and overlapped DEGs were acquired with Venn Diagrams. Functional enrichment analysis of overlapped DEGs and DEmiRNAs was conducted with Metascape and FunRich, respectively. The protein-protein interaction (PPI) network of overlapped DEGs was constructed by STRING and visualized with Cytoscape. Overall survival (OS) of DEmiRNAs and hub genes were investigated by Kaplan-Meier (KM) plotter (KM plotter). Transcriptional data and correlation analyses among hub genes were verified through GEPIA and Human Protein Atlas (HPA). Additionally, miRNA targets were searched using miRTarBase, then miRNA-DEG regulatory network was visualized with Cytoscape. A total of 32 DEmiRNAs and 150 overlapped DEGs were identified, and Metascape showed that DEGs were significantly enriched in cellular chemical homeostasis and pathways in cancer, while DEmiRNAs were mainly enriched in signal transduction and Glypican pathway. Moreover, seven hub genes with a high degree, namely, V-myc avian myelocytomatosis viral oncogene homolog (MYC), solute carrier family 2 member 1 (SLC2A1), PKM, plasminogen activator, urokinase (PLAU), peroxisome proliferator activated receptor gamma (PPARG), MET proto-oncogene, receptor tyrosine kinase (MET), and integrin subunit alpha 3 (ITGA3), were identified and found to be up-regulated between PDAC and normal tissues. miR-135b, miR-221, miR-21, miR-27a, miR-199b-5p, miR-143, miR-196a, miR-655, miR-455-3p, miR-744 and hub genes predicted poor OS of PDAC. An integrative bioinformatics analysis identified several hub genes that may serve as potential biomarkers or targets for early diagnosis and precision target treatment of PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":31220948,"Year":2019,"Title":"A new method for early detection of pancreatic cancer biomarkers: detection of microRNAs by nanochannels.","Abstract":"Objective: To develop an effective new method for early detection of pancreatic cancer biomarkers and to aid early clinical diagnosis. Methods: A DNA probe (Probe) capable of specifically recognizing the target miRNA was designed. The specific probe of miRNA 21 is designed first, and then mixed with the miRNA 21 sample to form a complex molecule, and the complex molecule is added to the nanochannels to detect the received signal. The probe is designed to detect the electrical signal by means of pre-matching and post-matching and observe the stability of the signal. The miRNA 21, miRNA 155, miRNA 196a were added to the nano-single channel to detect the characteristic signals and blocking time. The miRNA 21.probe 21 mixture was mixed with other five cancer-associated microRNAs, and the signal results of the detection were collected and compared. Results: The signal of miRNA 21 was successfully detected. Whether the probe is designed at the front or the back, there are two signal results. The Probe should be designed to match the middle region of the miRNA. The three microRNA complex molecules have different characteristic signals and blocking times, which can be effectively distinguished. Conclusion: Nanochannels can effectively detect pancreatic cancer-related microRNAs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":31009404,"Year":2019,"Title":"Novel Circulating miRNA Signatures for Early Detection of Pancreatic Neoplasia.","Abstract":"OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) presents the lowest survival rate of all cancers because only 6% of patients reach five-year survival. Alterations in the expression of several microRNAs (miRNAs) occur in the tumor of PDAC and in preneoplastic lesions as the called intraductal papillary mucinous neoplasm (IPMN). Here, we aimed at identifying which miRNAs are significantly altered in liquid biopsies from patients with PDAC and IPMN to find new noninvasive biomarkers for early detection of PDAC. METHODS: We analyzed by real-time quantitative reverse transcription-PCR (qRT-PCR) the expression of 17 circulating miRNAs, previously found to be significantly overexpressed in tissue pancreatic neoplasms, in a set of 182 plasma samples (94 PDAC, 19 IPMN, 18 chronic pancreatitis, and 51 disease-free controls). Then, we analyzed CA19.9 levels in the same plasma set, and we assessed the diagnostic values of differentially expressed miRNAs, CA19.9, and all possible combinations. RESULTS: Of note, 16, 14, and 9 miRNAs were significantly increased in PDAC, IPMN, and chronic pancreatitis, respectively, compared with control plasmas. miR-21-5p, miR-33a-3p, miR-320a, and miR-93-5p showed the highest discriminating capacity for pancreatic neoplasia (PDAC or IPMN) with an area under the receiver operating characteristic curve (AUC) of 0.86, 0.85, 0.85, and 0.80, respectively. 2-miRNA combinations improved these performances reaching AUC = 0.90 for \"miR-33a-3p+miR-320a.\" Addition of CA19.9 increased the diagnostic potential of miRNA signatures even further achieving an AUC of 0.95 (93% sensitivity and 85% specificity) for the combination of \"miR-33a-3p+miR-320a+CA19.9.\" CONCLUSIONS: Novel signatures combining miRNAs and CA19.9 could be used as noninvasive biomarkers for early detection of PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30820789,"Year":2019,"Title":"Pancreatic Juice Exosomal MicroRNAs as Biomarkers for Detection of Pancreatic Ductal Adenocarcinoma.","Abstract":"BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasm because of difficulties in early detection. Several studies have recently suggested that exosomes may have potential as novel biomarkers. This study aimed to isolate exosomes from pancreatic juice and to investigate whether exosomal microRNAs (ex-miRs) could be used as biomarkers for PDAC. METHODS: Pancreatic juice was collected from patients with PDAC and chronic pancreatitis (CP) by endoscopic retrograde pancreatography. Exosomes were extracted by ultracentrifugation. The presence of exosomes was confirmed by electron microscopy and Western blotting using anti-CD63, -CD81, and -TSG101 antibodies. Relative levels of ex-miR-21 and ex-miR-155 were quantified and compared between PDAC and CP patients. RESULTS: A total of 35 pancreatic juice samples (27 PDAC and 8 CP) were collected. Relative levels of both ex-miR-21 and ex-miR-155 were significantly higher in PDAC patients compared with CP patients (p < 0.001 and p = 0.008, respectively). By contrast, no significant difference was apparent in relative levels of miR-21 and miR-155 in whole pancreatic juice from PDAC patients compared with CP patients (p = 0.08 and p = 0.61, respectively). Ex-miR-21 and ex-miR-155 levels discriminated PDAC patients from CP patients with area under the curve values of 0.90 and 0.89, respectively. The accuracies of ex-miR-21 levels, ex-miR-155 levels, and pancreatic juice cytology were 83%, 89%, and 74%, respectively. When combining the results of ex-miR profiling with pancreatic juice cytology, the accuracy was improved to 91%. CONCLUSIONS: We successfully extracted exosomes from pancreatic juice. Ex-miRs, including ex-miR-21 and ex-miR-155, in pancreatic juice may be developed as biomarkers for PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30682689,"Year":2019,"Title":"Integrating PDA microtube waveguide system with heterogeneous CHA amplification strategy towards superior sensitive detection of miRNA.","Abstract":"Catalytic hairpin assembly (CHA) is a typical enzyme-free amplification strategy, in which the target can catalyze two hairpin probes to form a duplex and yield multiple outputs signal. However, the non-specific hybridization of two hairpin probes in CHA circuit usually occurred even in the absence of target, causing significant background leakage and impeding its practical applications in trace miRNA analysis. Herein, we proposed a novel heterogeneous CHA (hetero-CHA) design integrating with PDA microtube waveguide system, offering the advantages to enhance the target signal, but suppress the background leakage simultaneously. In hetero-CHA strategy, single-stranded targets are enriched nearby the surface of PDA microtube, facilitating the target-triggered CHA amplification and strand displacement reactions. In contrast, double-stranded DNA complexes formed by uncatalyzed hybridizations are isolated from PDA microtube, impeding the leakage signal. By combination with condensing enrichment effect, the proposed hetero-CHA probe exhibited high selectivity and sensitivity to miRNA target, giving a detection limit as low as 3.3 fM. More importantly, the proposed hetero-CHA probe can be applied directly to distinguish the expression of miRNA-21 in clinical serum of cancer patients (including lung, breast and pancreatic) from those of healthy human beings, favoring the cancer diagnosis and therapeutic evaluation.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30681889,"Year":2019,"Title":"SAV1, regulated by microRNA-21, suppresses tumor growth in colorectal cancer.","Abstract":"This study investigated the role and action of the Salvador 1 protein (SAV1, also called WW45) in colorectal cancer (CRC). For this, CRC SW480 and HCT116 cells were infected with lentiviruses of SAV1 overexpression vector (lenti-SAV1) and SAV1 short hairpin RNA (sh-SAV1) to overexpress and silence SAV1 respectively, or transfected with microRNA-21 (miR-21) mimic to overexpress miR-21. Relative mRNA levels of SAV1 and relative miR-21 levels in CRC tissues or cells were detected. The effects of SAV1 and miR-21 on cell proliferation and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and annexin V - fluorescein isothiocyanate (FITC) - propidium iodide (PI) flow cytometry, respectively. Our results revealed that SAV1 was downregulated in CRC tissues compared with the adjacent noncancerous tissues. Furthermore, SAV1 overexpression inhibited proliferation and promoted apoptosis in SW480 and HCT116 cells, whereas knockdown of SAV1 exerted the opposite effect. Additionally, the tumorigenesis of SW480 cells in xenografted mice was significantly inhibited by SAV1 overexpression but promoted by SAV1 knockdown. MiR-21 levels significantly and negatively correlated with SAV1 expression in CRC tissues. More importantly, miR-21 overexpression significantly abolished the SAV1-mediated inhibition of proliferation and stimulation of apoptosis of SW480. In conclusion, SAV1 suppresses tumor growth in CRC and is regulated by miR-21.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30537729,"Year":2018,"Title":"RNA-Seq Analyses of the Role of miR-21 in Acute Pancreatitis.","Abstract":"BACKGROUND/AIMS: Our previous study demonstrated that a deficiency of microRNA 21 (miR-21) protects mice from acute pancreatitis, yet the underlying molecular networks associated with miR-21 in pancreatitis and pancreatitis-associated lung injury remain unexplored. METHODS: We used next generation sequencing to analyze gene expression profiles of pancreatic tissues from wild-type (WT) and miR-21 knockout (KO) mice treated with caerulein by using a 1-day treatment protocol. The Database for Annotation, Visualization, and Integrated Discovery gene annotation tool and Ingenuity Pathway Analysis were used to analyze the molecular pathways, while quantitative real-time PCR, western blotting, and immunohistochemistry were used to explore the molecular mechanisms. RESULTS: We identified 152 differentially expressed genes (DEGs) in pancreata between WT and KO mice treated with caerulein. Cellular biogenesis and metabolism were the major pathways affected between WT and KO mice, whereas cell death and inflammatory response discriminated between WT and KO mice under acute pancreatitis. We validated 16 DEGs, consisting of 6 upregulated genes and 10 downregulated genes, involved in pancreatic injury. In particular, the upregulation of Pias3 and downregulation of Hmgb1 in KO pancreata coincided with a reduced severity of pancreatitis. In addition, we found Hmgb1 stimulation resulted in the overexpression of miR-21 in peripheral blood mononuclear cells, and deletion of miR-21 led to a reduction of caerulein-induced acute pancreatitis-associated lung injury by repressing Hmgb1 expression. CONCLUSION: Our data support the hypothesis that miR-21 modulates the inflammatory response during acute pancreatitis through the upregulation of Pias3 and downregulation of Hmgb1. Our findings further underscore a role for miR-21 in the promotion of acute pancreatitis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30464258,"Year":2018,"Title":"miR-21 promotes EGF-induced pancreatic cancer cell proliferation by targeting Spry2.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant cancer that lacks effective targets for therapy. Alteration of epidermal growth factor (EGF) expression has been recognized as an essential molecular event in pancreatic carcinogenesis. Accumulating studies have demonstrated that miRNAs play critical roles in EGF signaling regulation, tumor initiation, cell proliferation and apoptosis. Here, we demonstrated that miR-21 expression was induced by EGF in pancreatic cancer cells. miR-21 promoted EGF-induced proliferation, inhibited cell apoptosis and accelerated cell cycle progression. In vivo experiments confirmed the influence of miR-21 on tumor growth. Mechanistic studies revealed that miR-21 targeted MAPK/ERK and PI3K/AKT signaling pathways to modulate cell proliferation. In addition, Spry2 was proven to be a target of miR-21. Furthermore, miR-21 and Spry2 were significantly related to clinical features and may be valuable predictors of PDAC patient prognosis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30336280,"Year":2018,"Title":"Prognostic significance of circulating microRNA-21 expression in esophageal, pancreatic and colorectal cancers; a systematic review and meta-analysis.","Abstract":"BACKGROUND: Literature has shown that aberrantly expressed microRNAs may have implications in certain cancers. A wealth of studies signal potential prognostic role of microRNA-21 in GIT cancers. This meta-analysis quantitatively determines prognostic significance of circulating microRNA-21 in esophageal squamous cell carcinoma (ESCC), pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma (CRC). METHODS: Databases of Medline, Wiley online library, Cochrane library, Taylor and Francis Online, CINAHL, Springer, Proquest, ISI Web of knowledge, ScienceDirect, and Emerald were searched using MeSH terms serum/tissue microRNA-21, prognosis, esophagus squamous cell carcinoma, pancreatic ductal adenocarcinoma, colorectal cancer. A systematic algorithm was used that selected 15 relevant studies. Meta-analysis was conducted using forest plot and a summary effect model was employed. RESULTS: This meta-analysis reports significant prognostic value of miR-21 in predicting worse overall survival (OS) in ESCC, PDAC, and CRC with pooled hazard ratio (HR) of 3.49 (95% CI 2.58-4.71, p-value<0.01). Subgroup analysis for ESCC showed a pooled HR of 3.46 (95% CI 1.88-635, p value of <0.01), worse overall survival (OS) with the pooled HR of 3.14 (95% CI 2.22-4.43, p value<0.01) for CRC and a pooled HR of 3.77 (95% CI 1.63-8.73, p value<0.01) for PDAC. CONCLUSION: This research infers that microRNA-21 expression is a powerful prognostic tool. Expression of micro-RNA-21 is associated with poor OS and poorer disease-free survival in ESCC, PDAC and CRC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30299890,"Year":2018,"Title":"Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms","Abstract":"Objective: Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumors arising from the endocrine pancreas; however, their prognosis differs significantly upon their proliferative state, which is characterized by histopathological grading. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to identify miRNAs with altered expression upon proliferation which can be used as prognostic biomarkers in PanNENs. Methods: MiRNA expression profiles of 40 PanNENs were downloaded from Gene Expression Omnibus and were reanalyzed upon tumor grades (discovery cohort). Results of the reanalysis were confirmed by qRT-PCR analysis of five miRNAs on an independent validation cohort of 63 primary PanNEN samples. Cox proportional hazards survival regression models were fit for both univariate and multivariate analysis to determine the miRNAs' effect on progression-free and overall survival. Results: Nineteen miRNAs displayed differential expression between tumor grades. The altered expression of three out of five chosen miRNAs was successfully validated; hsa-miR-21, hsa-miR-10a and hsa-miR-106b were upregulated in more proliferative PanNENs compared to Grade 1 tumors. In univariate analysis, higher expression of tissue hsa-miR-21, hsa-miR-10a and hsa-miR-106b of primary PanNENs predicted worse progression-free and overall survival; however, multivariate analysis only confirmed the expression of hsa-miR-21 as an independent prognostic factor. Conclusions: The expression of hsa-miR-106b, hsa-miR-10a and especially hsa-miR-21 has prognostic relevance regarding progression-free and overall survival in patients with PanNENs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30225540,"Year":2018,"Title":"Circulating microRNA-99 family as liquid biopsy marker in pancreatic adenocarcinoma.","Abstract":"PURPOSE: Recently, we identified the microRNA-99 family as unfavorable prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to evaluate its value as circulating biomarker for PDAC. METHODS: Tissue and corresponding preoperative blood samples of 181 patients with PDAC UICC Stages I-IV (n = 90), intraductal papillary mucinous neoplasm (IPMN, n = 11), chronic pancreatitis (n = 40), pancreatic cystadenoma (n = 20), and age-matched healthy blood serum controls (n = 20) were collected between 2014 and 2017 prospectively. Expression of microRNA-21 as confirmatory marker and the microRNA-99 family, consisting of microRNA-99a, -99b, and -100, was analyzed by qRT-PCR. Target analysis of insulin-like growth factor 1 receptor (IGF1R) was performed using tissue array immunohistochemistry and Western blotting. RESULTS: Expression of microRNA-99 family members was significantly increased in macrodissected tumor tissue and corresponding blood serum samples (p < 0.05) of patients with PDAC of all stages. Correspondingly, its target protein IGF1R was upregulated (p < 0.001) in carcinoma tissue. Circulating and tissue-related microRNA-100 could well discriminate PDAC from healthy samples with area under the receiver operating characteristic (ROC) curve (AUC) values of 0.81 and 0.85, respectively. Low expression of circulating microRNA-100 was associated with significantly improved overall survival (p = 0.004) and recurrence-free survival (p = 0.03) in multivariate analyses. Circulating microRNA-21 was overexpressed in PDAC with fair discrimination between PDAC and healthy controls (AUC = 0.71) and decreased overall survival (p = 0.046) and recurrence-free survival (p = 0.03) in PDAC patients. CONCLUSIONS: Multivariate survival and ROC analyses identified circulating microRNA-100 as potential diagnostic and prognostic marker in PDAC patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30209066,"Year":2018,"Title":"The TLR7/8/9 Antagonist IMO-8503 Inhibits Cancer-Induced Cachexia.","Abstract":": Muscle wasting is a feature of the cachexia syndrome, which contributes significantly to the mortality of patients with cancer. We have previously demonstrated that miR-21 is secreted through extracellular vesicles (EV) by lung and pancreatic cancer cells and promotes JNK-dependent cell death through its binding to the TLR7 receptor in murine myoblasts. Here, we evaluate the ability of IMO-8503, a TLR7, 8, and 9 antagonist, to inhibit cancer-induced cachexia. Using EVs isolated from lung and pancreatic cancer cells and from patient plasma samples, we demonstrate that IMO-8503 inhibits cell death induced by circulating miRNAs with no significant toxicity. Intraperitoneal administration of the antagonist in a murine model for Lewis lung carcinoma (LLC-induced cachexia) strongly impaired several cachexia-related features, such as the expression of Pax7 as well as caspase-3 and PARP cleavage in skeletal muscles, and significantly prevented the loss of lean mass in tumor-bearing mice. IMO-8503 also impaired circulating miRNA-induced cell death in human primary myoblasts. Taken together, our findings strongly indicate that IMO-8503 serves as a potential therapy for the treatment of cancer cachexia. SIGNIFICANCE: Cancer-associated cachexia is a significant problem for patients with cancer that remain poorly understood, understudied, and inadequately treated; these findings report a potential new therapeutic for the treatment of TLR7-mediated cancer cachexia.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30006373,"Year":2018,"Title":"Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms.","Abstract":"Objective Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumors arising from the endocrine pancreas, however their prognosis differs significantly upon their proliferative state which is characterized by histopathological grading. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to identify miRNAs with altered expression upon proliferation which can be used as prognostic biomarkers in PanNENs. Methods MiRNA expression profiles of 40 PanNENs were downloaded from Gene Expression Omnibus and were reanalyzed upon tumor grades (discovery cohort). Results of the reanalysis were confirmed by qRT-PCR analysis of 5 miRNAs on an independent validation cohort of sixty three primary PanNEN samples. Cox proportional hazards survival regression model was fit for both univariate and multivariate analysis to determine the miRNAs' effect on progression-free and overall survival. Results 19 miRNAs displayed differential expression between tumor grades. The altered expression of 3 out of 5 chosen miRNAs was successfully validated; hsa-miR-21, hsa-miR-10a and hsa-miR-106b were up-regulated in more proliferative PanNENs compared to grade 1 tumors. In univariate analysis, higher expression of tissue hsa-miR-21, hsa-miR-10a and hsa-miR-106b expression of primary PanNENs predicted worse progression-free and overall survival, however multivariate analysis only confirmed the expression of hsa-miR-21 as an independent prognostic factor. Conclusions The expression of hsa-miR-106b, hsa-miR-10a and especially hsa-miR-21 has prognostic relevance regarding progression-free and overall survival in patients with PanNENs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":29976637,"Year":2018,"Title":"Pre-operative Plasma miR-21-5p Is a Sensitive Biomarker and Independent Prognostic Factor in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Surgical Resection.","Abstract":"Blood plasma microRNAs (miRNAs) are emerging as a clinically useful tool for non-invasive detection and prognosis estimation in various cancer types including pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to provide an independent validation of circulating miRNAs identified in previous studies as diagnostic and/or prognostic biomarkers in PDAC. Based on the literature search, 6 miRNAs were chosen as candidates for independent validation; miR-21-5p, miR-375, miR-155, miR-17-5p, miR-126-5p and miR-1290. Validation of these miRNAs was performed in a cohort of 25 patients with PDAC undergoing surgical resection and 24 healthy donors. Plasma levels of miRNAs were determined using quantitative real-time PCR. We confirmed significantly higher levels of all tested miRNA in blood plasma of PDAC patients in comparison to healthy controls with miR-21-5p showing the highest analytical performance (p<0.001; AUC>0.99). Increased levels of miR-21-5p (p=0.045) and miR-375 (p=0.013) were significantly associated with overall survival. Multivariate analysis demonstrated that miR-21-5p is a significant unfavorable prognostic factor independent on other clinical variables including adjuvant chemotherapy (hazard ratio 2.95; 95% CI 1.06-8.18; p=0.038). Our preliminary data indicate promising diagnostic and prognostic utility of plasma miR-21-5p in PDAC patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":29922178,"Year":2018,"Title":"Blood-Derived microRNAs for Pancreatic Cancer Diagnosis: A Narrative Review and Meta-Analysis.","Abstract":"microRNAs (miRNAs) have been reported to be aberrantly expressed in patients with pancreatic cancer. In present review we explored the biological roles of miRNAs in pancreatic cancer and their clinical value in diagnosis. In the systematic review, the potential value of miRNAs as biomarkers was investigated by reviewing the altered miRNA profiles reported in pancreatic cancer patients in 356 included studies. In the subsequent meta-analysis, we included 17 studies in early diagnosis of pancreatic cancer with a panel of altered miRNAs. The following results were obtained: pooled sensitivity of 0.88 (95% confidence interval [CI] 0.83-0.92), pooled specificity of 0.83 (95%CI 0.77-0.88), diagnostic odds ratio of 27 (95%CI 14-53), and area under the receiver operating characteristic curve of 0.90 (95%CI 0.88-0.93). To further explore the value of a single miRNA, the diagnostic value of miR-21 in PA was also demonstrated by the pooled sensitivity (0.90, 95% CI: 0.82-0.94), specificity (0.72, 95% CI: 0.57-0.83) as well as AUC (0.91 (95%CI 0.88-0.93). In conclusion, our findings suggest that aberrant miRNA expression in blood play an essential role in pancreatic cancer, and meta-analysis revealed blood-derived miRNAs as probable biomarkers for early diagnosis of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":29854071,"Year":2018,"Title":"Resveratrol Inhibits ROS-Promoted Activation and Glycolysis of Pancreatic Stellate Cells via Suppression of miR-21.","Abstract":"Activation of pancreatic stellate cells (PSCs) initiates pancreatic fibrosis in chronic pancreatitis and furnishes a niche that enhances the malignancy of pancreatic cancer cells (PCCs) in pancreatic ductal adenocarcinoma (PDAC). Resveratrol (RSV), a natural polyphenol, exhibits potent antioxidant and anticancer effects. However, whether and how RSV influences the biological properties of activated PSCs and the effects of these changes on tumor remain unknown. In the present study, we found that RSV impeded hydrogen peroxide-driven reactive oxygen species- (ROS-) induced activation, invasion, migration, and glycolysis of PSCs. In addition, miR-21 expression in activated PSCs was downregulated after RSV treatment, whereas the PTEN protein level increased. miR-21 silencing attenuated ROS-induced activation, invasion, migration, and glycolysis of PSCs, whereas the overexpression of miR-21 rescued the responses of PSCs treated with RSV. Moreover, RSV or N-acetyl-L-cysteine (NAC) administration or miR-21 knockdown in PSCs reduced the invasion and migration of PCCs in coculture, and the effects of RSV were partly reversed by miR-21 upregulation. Collectively, RSV inhibits PCC invasion and migration through suppression of ROS/miR-21-mediated activation and glycolysis in PSCs. Therefore, targeting miR-21-mediated glycolysis by RSV in tumor stroma may serve as a new strategy for clinical PDAC prevention or treatment.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":29731265,"Year":2018,"Title":"MiR-21 up-regulation in ampullary adenocarcinoma and its pre-invasive lesions.","Abstract":"Poor information is available on the molecular landscape characterizing the carcinogenetic process leading to ampullary carcinoma. MiR-21 is one of the most frequently up-regulated miRNAs in pancreatic adenocarcinoma, a tumor sharing similar molecular features with ampullary adenocarcinomas (AVCs), above all with the pancreatic-biliary type. We profiled, by in situ hybridization (ISH), miR-21 expression in a series of 26 AVCs, 50 ampullary dysplastic lesions (35 low-grade [LG-IEN] and 15 high-grade [HG-IEN]) and 10 normal duodenal mucosa samples. The same series was investigated by immunohistochemistry for beta-catenin, p53 and HER2 expression. HER2 gene amplification was evaluated by chromogenic in situ hybridization. To validate miR-21 ISH results we performed miR-21 qRT-PCR analysis in a series of 10 AVCs and their matched normal samples. All the normal control samples showed a negative or faint miR-21 expression, whereas a significant miR-21 up-regulation was observed during the carcinogenetic cascade (p<0.001), with 21/26 (80.8%) of cancer samples showing a miR-21 overexpression. In comparison to control samples, a significant overexpression was found in samples of LG-IEN (p=.0003), HG-IEN (p=.0001), and AVCs (p<0.0001). No significant difference in miR-21 overexpression was observed between LG-IEN, HG-IEN and AVCs. By qRT-PCR analysis, AVCs showed a 1.7-fold increase over the controls (p=.003). P53 was frequently dysregulated in both dysplastic and carcinoma samples (44 out of 76; 57.9%). A 20% (10/50) of dysplastic lesions and 11% (3/26) of carcinomas were characterized by a nuclear localization of beta-catenin. Only 2 AVCs (7.7%; both intestinal-type) showed a HER2 overexpression (both 2+), which corresponded to a HER2 gene amplification at CISH analysis. This is the first study demonstrating a miRNA dysregulation in the whole spectrum of ampullary carcinogenesis. MiR-21 overexpression is an early molecular event during ampullary carcinogenesis and its levels increase with the neoplastic progression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":29616134,"Year":2018,"Title":"MicroRNA-216b reduces growth, migration and invasion of pancreatic ductal adenocarcinoma cells by directly targeting rho-associated coiled-coil containing protein kinase 1.","Abstract":"Developments in cancer therapy have greatly improved the survival time for patients with pancreatic ductal adenocarcinoma (PDAC); however, the prognosis of patients with PDAC remains poor. Understanding the expression patterns and functions of microRNAs may provide strategies for the diagnosis and treatment of patients with PDAC. The present study aimed to explore the expression and functions of microRNA-216b (miR-216b) in PDAC. The expression of miR-216b in PDAC tissues and cell lines was quantified with reverse transcription-quantitative polymerase chain reaction. An miR-216b mimic was introduced into PDAC cells to induce the effects of miR-21b overexpression. The effects of miR-216b overexpression on growth, migration and invasion of PDAC cells were evaluated by cell proliferation assay, migration and invasion assays, respectively. The molecular mechanism underlying the suppressive effects of miR-216b on PDAC was also examined; a direct target gene of miR-216b, rho-associated coiled-coil containing protein kinase 1 (ROCK1), was downregulated by ROCK1 short interfering RNA to investigate the effects on growth, migration and invasion of PDAC cells. The present study revealed that miR-216b was significantly downregulated in PDAC tissues and cell lines. Overexpression of miR-216b inhibited growth, migration and invasion of PDAC cells in vitro. ROCK1 was identified as a direct target gene of miR-216b in pancreatic cancer and the downregulation of ROCK1 resembled the effects of miR-216b overexpression in PDAC cells. Taken together, miR-216b acted as a tumor suppressor in PDAC and may represent a novel therapeutic target in PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":29556365,"Year":2018,"Title":"UTMD-Promoted Co-Delivery of Gemcitabine and miR-21 Inhibitor by Dendrimer-Entrapped Gold Nanoparticles for Pancreatic Cancer Therapy.","Abstract":"Conventional chemotherapy of pancreatic cancer (PaCa) suffers the problems of low drug permeability and inherent or acquired drug resistance. Development of new strategies for enhanced therapy still remains a great challenge. Herein, we report a new ultrasound-targeted microbubble destruction (UTMD)-promoted delivery system based on dendrimer-entrapped gold nanoparticles (Au DENPs) for co-delivery of gemcitabine (Gem) and miR-21 inhibitor (miR-21i). Methods: In this study, Gem-Au DENPs/miR-21i was designed and synthesized. The designed polyplexes were characterized via transmission electron microscopy (TEM), Gel retardation assay and dynamic light scattering (DLS). Then, the optimum exposure parameters were examined by an ultrasound exposure platform. The cellular uptake, cytotoxicity and anticancer effects in vitro were analyzed by confocal laser microscopy, spectra microplate reader, flow cytometry and a chemiluminescence imaging system. Lastly, the anticancer effects in vivo were evaluated by contrast-enhanced ultrasound (CEUS), hematoxylin and eosin (H&E) staining, TUNEL staining and comparison of tumor volume. Results: The results showed that the Gem-Au DENPs/miR-21i can be uptake by cancer cells and the cellular uptake was further facilitated by UTMD with an ultrasound power of 0.4 W/cm(2) to enhance the cell permeability. Further, the co-delivery of Gem and miR-21i with or without UTMD treatment displayed 82-fold and 13-fold lower IC50 values than the free Gem, respectively. The UTMD-promoted co-delivery of Gem and miR-21i was further validated by in vivo treatment and showed a significant tumor volume reduction and an increase in blood perfusion of xenografted pancreatic tumors. Conclusion: The co-delivery of Gem and miR-21i using Au DENPs can be significantly promoted by UTMD technology, hence providing a promising strategy for effective pancreatic cancer treatments.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":29483829,"Year":2018,"Title":"MiR-21-mediated Metabolic Alteration of Cancer-associated Fibroblasts and Its Effect on Pancreatic Cancer Cell Behavior.","Abstract":"In this study, we investigated whether the metabolic alteration of cancer-associated fibroblasts (CAFs) occurs via miR-21 remodeling and the effect of this alteration on pancreatic cancer cells. CAFs and normal fibroblasts (NFs) were isolated and cultured. Glucose consumption and lactic acid production were tested, and lactate dehydrogenase (LDHA), pyruvate kinase m2 (PKM2), and miR-21 expression were examined. The level of glycolysis in CAFs was determined after treatment with a miR-21 inhibitor. Primary miR-21-NC CAFs and miR-21-inhibitor CAFs were indirectly co-cultured with BxPc-3 in vitro, and the invasion capacity of these cells was determined. The aerobic oxidation index of cancer cells and the expression of succinodehydrogenase (SDH) and fumarate hydratase (FH) were assessed. Compared with NFs, CAFs showed enhanced glucose uptake capacity, lactic acid production, and elevated LDHA, PKM2, and miR-21 expression. After miR-21 inhibitor treatment, the extent of glycolysis in CAFs was reduced. After indirect co-culture with CAFs, oxidative phosphorylation and SDH, FH, and MCT expression increased in BxPc-3 cells. After co-culture with miR-21-inhibitor-CAFs, oxidative phosphorylation and invasion ability of the pancreatic cancer cells decreased. MiR-21 was involved in metabolic alteration of CAFs and affected the development of cancer cells. This metabolic alteration may be an important mechanism by which the microenvironment promotes tumor progression in a nonvascular manner.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":29464088,"Year":2018,"Title":"Deciphering microRNA targets in pancreatic cancer using miRComb R package.","Abstract":"MiRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. They play important roles in cancer but little is known about the specific functions that each miRNA exerts in each type of cancer. More knowledge about their specific targets is needed to better understand the complexity of molecular networks taking part in cancer. In this study we report the miRNA-mRNA interactome occurring in pancreatic cancer by using a bioinformatic approach called miRComb, which combines tissue expression data with miRNA-target prediction databases (TargetScan, miRSVR and miRDB). MiRNome and transcriptome of 12 human pancreatic tissues (9 pancreatic ductal adenocarcinomas and 3 controls) were analyzed by next-generation sequencing and microarray, respectively. Analysis confirmed differential expression of both miRNAs and mRNAs in cancerous tissue versus control, and unveiled 17401 relevant miRNA-mRNA interactions likely to occur in pancreatic cancer. They were sorted according to the degree of negative correlation between miRNA and mRNA expression. Results highlighted the importance of miR-148a and miR-21 interactions among others. Two components of the Notch signaling pathway, ADAM17 and EP300, were confirmed as miR-148a targets in MiaPaca-2 pancreatic cancer cells overexpressing miR-148a. Moreover, a CRISPR-Cas9 cellular model was generated to knock-out the expression of miR-21 in PANC-1 cells. As expected, the expression of two miRComb miR-21 predicted targets, PDCD4 and BTG2, was significantly upregulated in these cells in comparison to control PANC-1.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":29385987,"Year":2018,"Title":"An elevated expression of serum exosomal microRNA-191, - 21, -451a of pancreatic neoplasm is considered to be efficient diagnostic marker.","Abstract":"BACKGROUND: Pancreatic cancer is associated with an extremely poor prognosis, so new biomarkers that can detect the initial stages are urgently needed. The significance of serum microRNA (miR) levels in pancreatic neoplasm such as pancreatic cancer and intraductal papillary mucinous neoplasm (IPMN) diagnosis remains unclear. We herein evaluated the usefulness of miRs enclosed in serum exosomes (ExmiRs) as diagnostic markers. METHODS: The ExmiRs from patients with pancreatic cancer (n = 32) or IPMN (n = 29), and patients without neoplasms (controls; n = 22) were enriched using ExoQuick-TC. The expression of ExmiRs was evaluated using a next-generation sequencing analysis, and the selected three miRs through this analysis were confirmed by a quantitative real-time polymerase chain reaction. RESULTS: The expression of ExmiR-191, ExmiR-21 and ExmiR-451a was significantly up-regulated in patients with pancreatic cancer and IPMN compared to the controls (p < 0.05). A receiver operating characteristic curve analysis showed that the area under the curve and the diagnostic accuracy of ExmiRs were 5-20% superior to those of three serum bulky circulating miRs (e.g.; ExmiR-21: AUC 0.826, accuracy 80.8%. Circulating miR-21: AUC 0.653, accuracy 62.3%). In addition, high ExmiR-451a was associated with mural nodules in IPMN (p = 0.010), and high ExmiR-21 was identified as a candidate prognostic factor for the overall survival (p = 0.011, HR 4.071, median OS of high-ExmiR-21: 344 days, median OS of low-ExmiR-21: 846 days) and chemo-resistant markers (p = 0.022). CONCLUSIONS: The level of three ExmiRs can thus serve as early diagnostic and progression markers of pancreatic cancer and IPMN, and considered more useful markers than the circulating miRs (limited to these three miRs).","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28660759,"Year":2017,"Title":"DNA Tetrahedral Nanostructure-Based Electrochemical miRNA Biosensor for Simultaneous Detection of Multiple miRNAs in Pancreatic Carcinoma.","Abstract":"Specific and sensitive biomarker detection is essential to early cancer diagnosis. In this study, we demonstrate an ultrasensitive electrochemical biosensor with the ability to detect multiple pancreatic carcinoma (PC)-related microRNA biomarkers. By employing DNA tetrahedral nanostructure capture probes to enhance the detection sensitivity as well as a disposable 16-channel screen-printed gold electrode (SPGE) detection platform to enhance the detection efficiency, we were able to simultaneously detect four PC-related miRNAs: miRNA21, miRNA155, miRNA196a, and miRNA210. The detection sensitivity reached to as low as 10 fM. We then profiled the serum levels of the four miRNAs for PC patients and healthy individuals with our multiplexing electrochemical biosensor. Through the combined analyses of the four miRNAs, our results showed that PC patients could be discriminated from healthy controls with fairly high sensitivity. This multiplexing PCR-free miRNA detection sensor shows promising applications in early diagnosis of PC disease.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28548126,"Year":2017,"Title":"MicroRNA dysregulation in the tumor microenvironment influences the phenotype of pancreatic cancer.","Abstract":"Cellular interactions in the tumor microenvironment influence neoplastic progression in pancreatic ductal adenocarcinoma. One underlying mechanism is the induction of the prognostically unfavorable epithelial-mesenchymal-transition-like tumor budding. Our aim is to explore the expression of microRNAs implicated in the regulation of tumor budding focusing on the microenvironment of the invasive front. To this end, RNA from laser-capture-microdissected material of the main tumor, tumor buds, juxta-tumoral stroma, tumor-remote stroma, and non-neoplastic pancreatic parenchyma from pancreatic cancer cases with (n=7) and without (n=6) tumor budding was analyzed by qRT-PCR for the expression of a panel of miRNAs that are known to be implicated in the regulation of epithelial-mesenchymal transition, including miR-21, miR-183, miR-200b, miR-200c, miR-203, miR-205, miR-210, and miR-217. Here we show that at the invasive front of pancreatic ductal adenocarcinoma, specific microRNAs, are differentially expressed between tumor buds and main tumor cells and between cases with and without tumor budding, indicating their involvement in the regulation of the budding phenotype. Notably, miR-200b and miR-200c were significantly downregulated in the tumor buds. Consistent with this finding, they negatively correlated with the expression of epithelial-mesenchymal-transition-associated E-cadherin repressors ZEB1 and ZEB2 in the budding cells (P<0.001). Interestingly, many microRNAs were also dysregulated in juxta-tumoral compared to tumor-remote stroma suggesting that juxta-tumoral stroma contributes to microRNA dysregulation. Notably, miR-200b and miR-200c were strongly downregulated while miR-210 and miR-21 were upregulated in the juxta-tumoral vs tumor-remote stroma in carcinomas with tumor budding. In conclusion, microRNA targeting in both tumor and stromal cells could represent a treatment option for aggressive pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28542740,"Year":2017,"Title":"Plasma microRNAs as biomarkers of pancreatic cancer risk in a prospective cohort study.","Abstract":"Noninvasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case-control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate prediagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR-10a, -10b, -21-3p, -21-5p, -30c, -106b, -155 and -212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status and age/date/time of blood collection. MiR levels in prediagnostic plasma samples were determined by quantitative RT-PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR-10b, -21-5p, -30c and -106b levels were significantly higher in cases diagnosed within 2 years of blood collection compared to matched controls (all p-values <0.04). Based on adjusted logistic regression models, levels for six miRs (miR-10a, -10b, -21-5p, -30c, -155 and -212) overall, and for four miRs (-10a, -10b, -21-5p and -30c) at shorter follow-up time between blood collection and diagnosis (<\/=5 yr, <\/=2 yr), were statistically significantly associated with risk. A score based on the panel showed a linear dose-response trend with risk (p-value = 0.0006). For shorter follow-up (<\/=5 yr), AUC for the score was 0.73, and for individual miRs ranged from 0.73 (miR-212) to 0.79 (miR-21-5p).","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28490741,"Year":2017,"Title":"Circulating miRNA-21-5p as a diagnostic biomarker for pancreatic cancer: evidence from comprehensive miRNA expression profiling analysis and clinical validation.","Abstract":"Pancreatic cancer (PC) is a highly fatal disease worldwide and is often misdiagnosed in its early stages. The exploration of novel non-invasive biomarkers will definitely benefit PC patients. Recently, circulating miRNAs in body fluids are emerging as non-invasive biomarkers for PC diagnosis. In this study, we first conducted comprehensive robust rank aggregation (RRA) analysis based on 21 published miRome profiling studies. We statistically identified and clinically validated a miRNA expression pattern in PC patients. These miRNAs consisted of four up-regulated (hsa-miR-21-5p, hsa-miR-31-5p, hsa-miR-210-3p and hsa-miR-155-5p) and three down-regulated miRNAs (hsa-miR-217, hsa-miR-148a-3p and hsa-miR-375). Among them, hsa-miR-21-5p was one of the most highly expressed miRNAs in the serum of PC patients. Our validation test further suggested a relatively high accuracy of serum hsa-miR-21-5p levels in the diagnosis of PC, with a sensitivity of 0.77 and a specificity of 0.80. Finally, a diagnostic meta-analysis based on 9 studies also revealed favorable sensitivity and specificity of circulating hsa-miR-21-5p for the diagnosis of PC (pooled sensitivity and specificity were 0.76 and 0.74, respectively), which was consistent with our findings. Taken together, as one of the most aberrantly expressed miRNAs in PC, circulating hsa-miR-21-5p might be a promising serum biomarker in patients with PC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28477403,"Year":2018,"Title":"Micro-RNA-21 Regulates Cancer-Associated Fibroblast-Mediated Drug Resistance in Pancreatic Cancer.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer deaths due to its highly aggressive biological nature and resistance to chemotherapy. Previous studies indicate that miR-21 is an important regulator in the activation of cancer-associated fibroblasts (CAFs). However, whether miR-21 in CAFs would regulate PDAC's tumor microenvironment and lead to drug resistance remain unknown. In this study, we evaluated the relationship between CAF activation, miR-21 expression, and drug resistance using tumor samples from PDAC patients. We changed the miR-21 expression level in CAFs and tested its roles in regulating the function of CAFs. In addition, we explored the roles of miR-21 in CAFs in the development of PDAC using an animal model. We found that PDAC patients who were resistant to gemcitabine treatment tended to have higher miR-21 expression and more activated CAFs. An in vitro study showed that CAFs with high miR-21 expression had elevated MMP-3, MMP-9, PDGF, and CCL-7 expression and promoted the invasion of PDAC cell lines. miR-21 overexpression also contributed to the activation of CAFs by regulating the PDCD4 gene. The in vivo study showed that upregulating miR-21 in CAFs promoted PDAC desmoplasia and increased its drug resistance to gemcitabine treatment, but downregulating miR-21 in CAFs suppressed desmoplasia and enhanced the effect of gemcitabine. We concluded that miR-21 promoted the activation of CAFs and contributed to the drug resistance of PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28466015,"Year":2017,"Title":"Evaluation of Plasma MicroRNAs as Diagnostic and Prognostic Biomarkers in Pancreatic Adenocarcinoma: miR-196a and miR-210 Could Be Negative and Positive Prognostic Markers, Respectively.","Abstract":"Background. Identifying diagnostic and prognostic biomarkers that could be targeted in the therapy of pancreatic cancer is essential. Objective. Investigations were conducted with respect to plasma miRNA (miR-21, miR-210, miR-155, miR-196a, miR-20a, and miR-25) expression and clinicopathologic factors to evaluate the prognostic value of miRNAs in pancreatic ductal adenocarcinoma (PDAC). Methods. Plasma miRNAs were detected by real-time quantitative PCR, and the association with clinicopathologic factors was subsequently performed by univariate and multivariate analyses. Results. Six miRNAs expressed significantly higher in PDAC patients than in normal individuals were identified. Receiver operating characteristic (ROC) curves were constructed. It was evident that miRNA expression associated with PDAC, lymph node metastasis, serosal infiltration, and comprehensive therapy reached significance for overall survival. High miR-196a expression was associated with poor survival (P = 0.001), whereas high miR-210 expression was significantly associated with improved survival (P = 0.003). Multivariate survival analysis indicated that the miR-210 and miR-196a expression signature, lymph node metastasis, and comprehensive therapy were independent factors affecting overall survival. Conclusions. MiRNA expression profile is distinctive in PDAC. Aberrant expression of certain miRNAs was remarkably involved in shaping the overall survival time, which include miR-196a overexpression and decreased miR-210 expression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28444967,"Year":2017,"Title":"Co-delivery of microRNA-21 antisense oligonucleotides and gemcitabine using nanomedicine for pancreatic cancer therapy.","Abstract":"Tumor metastasis occurs naturally in pancreatic cancer, and the efficacy of chemotherapy is usually poor. Precision medicine, combining downregulation of target genes with chemotherapy drugs, is expected to improve therapeutic effects. Therefore, we developed a combined therapy of microRNA-21 antisense oligonucleotides (ASO-miR-21) and gemcitabine (Gem) using a targeted co-delivery nanoparticle (NP) carrier and investigated the synergistic inhibitory effects on pancreatic cancer cells metastasis and growth. Polyethylene glycol-polyethylenimine-magnetic iron oxide NPs were used to co-deliver ASO-miR-21 and Gem. An anti-CD44v6 single-chain variable fragment (scFvCD44v6 ) was used to coat the particles to obtain active and targeted delivery. Our results showed that the downregulation of the oncogenic miR-21 by ASO resulted in upregulation of the tumor-suppressor genes PDCD4 and PTEN and the suppression of epithelial-mesenchymal transition, which inhibited the proliferation and induced the clonal formation, migration, and invasion of pancreatic cancer cells in vitro. The co-delivery of ASO-miR-21 and Gem induced more cell apoptosis and inhibited the growth of pancreatic cancer cells to a greater extent than single ASO-miR-21 or Gem treatment in vitro. In animal tests, more scFvCD44v6 -PEG-polyethylenimine/ASO-magnetic iron oxide NP/Gem accumulated at the tumor site than non-targeted NPs and induced a potent inhibition of tumor proliferation and metastasis. Magnetic resonance imaging was used to observed tumor homing of NPs. These results imply that the combination of miR-21 gene silencing and Gem therapy using an scFv-functionalized NP carrier exerted synergistic antitumor effects on pancreatic cancer cells, which is a promising strategy for pancreatic cancer therapy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28382422,"Year":2018,"Title":"The Role of Exosomes in Pancreatic Cancer Microenvironment.","Abstract":"Exosomes are nanovesicles shed by cells as a means of communication with other cells. Exosomes contain mRNAs, microRNAs (miRs) and functional proteins. In the present paper, we develop a mathematical model of tumor-immune interaction by means of exosomes shed by pancreatic cancer cells and dendritic cells. Cancer cells' exosomes contain miRs that promote their proliferation and that inhibit immune response by dendritic cells, and by CD4+ and CD8+ T cells. Dendritic cells release exosomes with proteins that induce apoptosis of cancer cells and that block regulatory T cells. Simulations of the model show how the size of the pancreatic cancer can be determined by measurement of specific miRs (miR-21 and miR-203 in the case of pancreatic cancer), suggesting these miRs as biomarkers for cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28304379,"Year":2017,"Title":"Development of bioluminescent chick chorioallantoic membrane (CAM) models for primary pancreatic cancer cells: a platform for drug testing.","Abstract":"The aim of the present study was to develop chick-embryo chorioallantoic membrane (CAM) bioluminescent tumor models employing low passage cell cultures obtained from primary pancreatic ductal adenocarcinoma (PDAC) cells. Primary PDAC cells transduced with lentivirus expressing Firefly-luciferase (Fluc) were established and inoculated onto the CAM membrane, with >80% engraftment. Fluc signal reliably correlated with tumor growth. Tumor features were evaluated by immunohistochemistry and genetic analyses, including analysis of mutations and mRNA expression of PDAC pivotal genes, as well as microRNA (miRNA) profiling. These studies showed that CAM tumors had histopathological and genetic characteristic comparable to the original tumors. We subsequently tested the modulation of key miRNAs and the activity of gemcitabine and crizotinib on CAM tumors, showing that combination treatment resulted in 63% inhibition of tumor growth as compared to control (p < 0.01). These results were associated with reduced expression of miR-21 and increased expression of miR-155. Our study provides the first evidence that transduced primary PDAC cells can form tumors on the CAM, retaining several histopathological and (epi)genetic characteristics of original tumors. Moreover, our results support the use of these models for drug testing, providing insights on molecular mechanisms underlying antitumor activity of new drugs/combinations.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28239461,"Year":2017,"Title":"Tissue MicroRNA profiles as diagnostic and prognostic biomarkers in patients with resectable pancreatic ductal adenocarcinoma and periampullary cancers.","Abstract":"BACKGROUND: The aim of this study was to validate previously described diagnostic and prognostic microRNA expression profiles in tissue samples from patients with pancreatic cancer and other periampullary cancers. METHODS: Expression of 46 selected microRNAs was studied in formalin-fixed paraffin-embedded tissue from patients with resected pancreatic ductal adenocarcinoma (n = 165), ampullary cancer (n=59), duodenal cancer (n = 6), distal common bile duct cancer (n = 21), and gastric cancer (n = 20); chronic pancreatitis (n = 39); and normal pancreas (n = 35). The microRNAs were analyzed by PCR using the Fluidigm platform. RESULTS: Twenty-two microRNAs were significantly differently expressed in patients with pancreatic cancer when compared to healthy controls and chronic pancreatitis patients; 17 miRNAs were upregulated (miR-21-5p, -23a-3p, -31-5p, -34c-5p, -93-3p, -135b-3p, -155-5p, -186-5p, -196b-5p, -203, -205-5p, -210, -222-3p, -451, -492, -614, and miR-622) and 5 were downregulated (miR-122-5p, -130b-3p, -216b, -217, and miR-375). MicroRNAs were grouped into diagnostic indices of varying complexity. Ten microRNAs associated with prognosis were identified (let-7 g, miR-29a-5p, -34a-5p, -125a-3p, -146a-5p, -187, -205-5p, -212-3p, -222-5p, and miR-450b-5p). Prognostic indices based on differences in expression of 2 different microRNAs were constructed for pancreatic and ampullary cancer combined and separately (30, 5, and 21 indices). CONCLUSION: The study confirms that pancreatic cancer tissue has a microRNA expression profile that is different from that of other periampullary cancers, chronic pancreatitis, and normal pancreas. We identified prognostic microRNAs and microRNA indices that were associated with shorter overall survival in patients with radically resected pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28232049,"Year":2017,"Title":"A microRNA signature in circulating exosomes is superior to exosomal glypican-1 levels for diagnosing pancreatic cancer.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that often presents clinically at an advanced stage and that may be confused with chronic pancreatitis (CP). Conversely, CP may be misdiagnosed as PDAC leading to unwarranted pancreas resection. Therefore, early PDAC diagnosis and clear differentiation between PDAC and CP are crucial for improved care. Exosomes are circulating microvesicles whose components can serve as cancer biomarkers. We compared exosomal glypican-1 (GPC1) and microRNA levels in normal control subjects and in patients with PDAC and CP. We report that exosomal GPC1 is not diagnostic for PDAC, whereas high exosomal levels of microRNA-10b, (miR-10b), miR-21, miR-30c, and miR-181a and low miR-let7a readily differentiate PDAC from normal control and CP samples. By contrast with GPC1, elevated exosomal miR levels decreased to normal values within 24 h following PDAC resection. All 29 PDAC cases exhibited significantly elevated exosomal miR-10b and miR-30c levels, whereas 8 cases had normal or slightly increased CA 19-9 levels. Thus, our exosomal miR signature is superior to exosomal GPC1 or plasma CA 19-9 levels in establishing a diagnosis of PDAC and differentiating between PDAC and CP.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":28186267,"Year":2017,"Title":"MicroRNA-196b is an independent prognostic biomarker in patients with pancreatic cancer.","Abstract":"Pancreatic cancer is a highly aggressive malignancy, with <50% patients surviving beyond 6 months after the diagnosis, and thus, there is an urgent need to explore new diagnostic and therapeutic approaches for this disease. Therefore, we conducted microRNA (miRNA) array analysis to detect miRNA molecules potentially associated with pancreatic cancer malignancy. To assess the identified miRNAs, we performed quantitative reverse transcription-PCR on 248 pancreatic ductal adenocarcinomas (UICC stage II). We also examined miRNA expression [microRNA-21 (miR-21) and microRNA-31 (miR-31)] and epigenetic alterations, including CpG island methylator phenotype (CIMP), potentially associated with the identified miRNAs. For functional analysis, we conducted proliferation and invasion assays using a pancreatic cancer cell line. miRNA array analysis revealed that microRNA-196b (miR-196b) was the most up-regulated miRNA in pancreatic cancer tissues compared with normal pancreatic duct cells. High miR-196b expression was associated with miR-21 (P = 0.0025) and miR-31 (P = 0.0001) expression. It was also related to poor prognosis in the multivariate analysis using overall survival (hazard ratio: 1.66; 95% confidence interval: 1.09-2.54; P = 0.019). Functional analysis demonstrated that miR-196b inhibitor decreased cell proliferation and that miR-196b mimic promoted cancer cell invasion. In conclusion, a significant association of high miR-196b expression with poor prognosis was observed in pancreatic cancer. Our data also revealed that miR-196b played an oncogenic role and that the transfection of the miR-196b inhibitor had an anti-tumour effect in the pancreatic cancer cell line. These results suggest that miR-196b is a promising diagnostic biomarker and therapeutic target in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":27894092,"Year":2016,"Title":"A novel fully human anti-NCL immunoRNase for triple-negative breast cancer therapy.","Abstract":"Breast cancer is the most common cancer in women worldwide. A new promising anti-cancer therapy involves the use of monoclonal antibodies specific for target tumor-associated antigens (TAAs). A TAA of interest for immunotherapy of Triple Negative Breast Cancer (TNBC) is nucleolin (NCL), a multifunctional protein, selectively expressed on the surface of cancer cells, which regulates the biogenesis of specific microRNAs (miRNAs) involved in tumor development and drug-resistance. We previously isolated a novel human anti-NCL scFv, called 4LB5, that is endowed with selective anti-tumor effects. Here we report the construction and characterization of a novel immunoRNase constituted by 4LB5 and a human pancreatic RNase (HP-RNase) called \"4LB5-HP-RNase\". This immunoRNase retains both the enzymatic activity of human pancreatic RNase and the specific binding of the parental scFv to a panel of surface NCL-positive breast cancer cells. Notably, 4LB5-HP-RNase dramatically and selectively reduced the viability and proliferation of NCL-positive tumor cells in vitro and in vivo. Specifically, it induced apoptosis and reduced the levels of the tumorigenic miRNAs miR-21, -221 and -222. Thus, this novel immunoagent could be a valuable tool for the treatment of TNBC patients ineligible for currently available targeted treatments.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":27841793,"Year":2017,"Title":"Exosomes Derived From Pancreatic Stellate Cells: MicroRNA Signature and Effects on Pancreatic Cancer Cells.","Abstract":"OBJECTIVES: Pancreatic stellate cells (PSCs) interact with pancreatic cancer cells in the tumor microenvironment. Cell constituents including microRNAs may be exported from cells within membranous nanovesicles termed exosomes. Exosomes might play a pivotal role in intercellular communication. This study aimed to clarify the microRNA signature of PSC-derived exosomes and their effects on pancreatic cancer cells. METHODS: Exosomes were prepared from the conditioned medium of immortalized human PSCs. MicroRNAs were prepared from the exosomes and their source PSCs, and the microRNA expression profiles were compared by microarray. The effects of PSC-derived exosomes on proliferation, migration, and the mRNA expression profiles were examined in pancreatic cancer cells. RESULTS: Pancreatic stellate cell-derived exosomes contained a variety of microRNAs including miR-21-5p. Several microRNAs such as miR-451a were enriched in exosomes compared to their source PSCs. Pancreatic stellate cell-derived exosomes stimulated the proliferation, migration and expression of mRNAs for chemokine (C - X - C motif) ligands 1 and 2 in pancreatic cancer cells. The stimulation of proliferation, migration, and chemokine gene expression by the conditioned medium of PSCs was suppressed by GW4869, an exosome inhibitor. CONCLUSIONS: We clarified the microRNA expression profile in PSC-derived exosomes. Pancreatic stellate cell-derived exosomes might play a role in the interactions between PSCs and pancreatic cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":27713117,"Year":2016,"Title":"New combined microRNA and protein plasmatic biomarker panel for pancreatic cancer.","Abstract":"INTRODUCTION: Lack of diagnostic makers results in loss of operation opportunity in that most patients are diagnosed at the late stage. Pancreatic cancer (PC) has been regarded as a fatal disease with a 5-year survival rate below 10%. Therefore, the development of diagnostic biomarkers for PC is in urgent need to control the mortality of the disease. MATERIALS AND METHODS: This is a case-control study including 640 plasma samples from healthy controls (HC), patients with benign pancreatic diseases (BPD), patients with PC; and patients with other gastrointestinal (GI) cancers. Eight biomarker candidates, including miR-20a, miR-21, miR-25, miR-155, miR-196a, miR-210, Macrophage Inhibitory Cytokine-1(MIC-1) and CA19-9, were evaluated to establish two diagnostic indexes in this study. RESULTS: The plasma level of the six miRNAs and MIC-1, CA19-9 were elevated in PC patients compared with those of healthy controls (P<0.001). Among them, miR-20a, miR-21, miR-25, MIC-1 and CA19-9 could distinguish PC patients from those with other GI cancers or BPD. With multivariable logistic regression, we established two specific indexes for diagnosis of PC(Index1 contains miR-21, MIC-1 and CA19-9; Index2 contains miR-25, MIC-1 and CA19-9). In a randomized setting of 260 HC, 168 PC, 132 other GI cancers and 80 BPD patients, both indexes performed not only better sensitivity for PC but also better specificity to distinguish PC from other GI cancers than CA19-9 and individual biomarkers. CONCLUSIONS: These results indicated that combination of biomarkers as a panel could improve diagnostic values compared with using a single marker. Such panels as illustrated in this study could provide novel plasmatic biomarker for PC diagnosis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":27475963,"Year":2016,"Title":"PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential.","Abstract":"BACKGROUND: Neoplastic stroma is believed to influence tumour progression. Here, we examine phosphatase and tensin homolog deleted on chromosome ten (PTEN) status in the tumour microenvironment of pancreatic ductal adenocarcinoma (PDAC) focussing especially at the stromal cells. METHODS: We asses PTEN at protein, messenger RNA and DNA level using a well-characterised PDAC cohort (n = 117). miR-21, known to target PTEN, is assessed after RNA extraction from different laser-capture-microdissected cell populations, including cancer cells and juxta-tumoural and tumour-remote stroma. RESULTS: PTEN deletion was the most frequent cause of PTEN protein loss in PDAC cells (71%) and correlated with vascular invasion (p = 0.0176) and decreased overall survival (p = 0.0127). Concomitant PTEN protein loss in tumour and juxta-tumoural stroma, found in 21.4% of PDACs, correlated with increased distant metastasis (p = 0.0045). Stromal cells with PTEN protein loss frequently showed PTEN genetic aberrations, including hemizygous PTEN deletion (46.6%) or chromosome 10 monosomy (40%). No alterations were found in the tumour-remote stroma. miR-21 was overexpressed by cancer- and juxta-tumoural stromal cells, in some cases without simultaneous PTEN gene alterations. No PTEN mutations or promoter methylation were detected. CONCLUSIONS: We find various mechanisms of PTEN protein loss in the different tumour cell populations, including allelic PTEN deletions, gross chromosomal 10 aberrations and altered miR-21 expression. PTEN deletion is a major cause of PTEN protein loss in PDAC and correlates with aggressive characteristics and worse outcome. PTEN protein loss in juxta-tumoural stromal cells is mostly due to PTEN haplo-insufficiency and characterises a subgroup of PDACs with enhanced metastatic potential. In the tumour microenvironment of the invasive front, PTEN silencing by miR-21 in cancer and surrounding stromal cells acts not only cooperatively but also independently of the genetic aberrations to precipitate PTEN protein loss and promote further tumour growth.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":27471839,"Year":2016,"Title":"A Highly Predictive Model for Diagnosis of Colorectal Neoplasms Using Plasma MicroRNA: Improving Specificity and Sensitivity.","Abstract":"OBJECTIVE: To develop a plasma-based microRNA (miRNA) diagnostic assay specific for colorectal neoplasms, building upon our prior work. BACKGROUND: Colorectal neoplasms [colorectal cancer (CRC) and colorectal advanced adenoma (CAA)] frequently develop in individuals at ages when other common cancers also occur. Current screening methods lack sensitivity, specificity, and have poor patient compliance. METHODS: Plasma was screened for 380 miRNAs using microfluidic array technology from a \"Training\" cohort of 60 patients, (10 each) control, CRC, CAA, breast cancer, pancreatic cancer, and lung cancer. We identified uniquely dysregulated miRNAs specific for colorectal neoplasia (P < 0.05, false discovery rate: 5%, adjusted alpha = 0.0038). These miRNAs were evaluated using single assays in a \"Test\" cohort of 120 patients. A mathematical model was developed to predict blinded sample identity in a 150 patient \"Validation\" cohort using repeat-sub-sampling validation of the testing dataset with 1000 iterations each to assess model detection accuracy. RESULTS: Seven miRNAs (miR-21, miR-29c, miR-122, miR-192, miR-346, miR-372, and miR-374a) were selected based upon P value, area under the curve (AUC), fold change, and biological plausibility. Area under the curve (+/-95% confidence interval) for \"Test\" cohort comparisons were 0.91 (0.85-0.96) between all neoplasia and controls, 0.79 (0.70-0.88) between colorectal neoplasia and other cancers, and 0.98 (0.96-1.0) between CRC and colorectal adenomas. In our \"Validation\" cohort, our mathematical model predicted blinded sample identity with 69% to 77% accuracy, 67% to 76% accuracy, and 86% to 90% accuracy for each comparison, respectively. CONCLUSIONS: Our plasma miRNA assay and prediction model differentiate colorectal neoplasia from patients with other neoplasms and from controls with higher sensitivity and specificity compared with current clinical standards.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":27471627,"Year":2016,"Title":"miRNA dynamics in tumor-infiltrating myeloid cells modulating tumor progression in pancreatic cancer.","Abstract":"Myeloid cells including tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC) are known as important mediators of tumor progression in solid tumors such as pancreatic cancer. Infiltrating myeloid cells have been identified not only in invasive tumors, but also in early pre-invasive pancreatic intraepithelial precursor lesions (PanIN). The functional dynamics of myeloid cells during carcinogenesis is largely unknown. We aimed to systematically elucidate phenotypic and transcriptional changes in infiltrating myeloid cells during carcinogenesis and tumor progression in a genetic mouse model of pancreatic cancer. Using murine pancreatic myeloid cells isolated from the genetic mouse model at different time points during carcinogenesis, we examined both established markers of macrophage polarization using RT-PCR and FACS as well as transcriptional changes focusing on miRNA profiling. Myeloid cells isolated during carcinogenesis showed a simultaneous increase of established markers of M1 and M2 polarization during carcinogenesis, indicating that phenotypic changes of myeloid cells during carcinogenesis do not follow the established M1/M2 classification. MiRNA profiling revealed distinct regulations of several miRNAs already present in myeloid cells infiltrating pre-invasive PanIN lesions. Among them miRNA-21 was significantly increased in myeloid cells surrounding both PanIN lesions and invasive cancers. Functionally, miRNA-21-5p and -3p altered expression of the immune-modulating cytokines CXCL-10 and CCL-3 respectively. Our data indicate that miRNAs are dynamically regulated in infiltrating myeloid cells during carcinogenesis and mediate their functional phenotype by facilitating an immune-suppressive tumor-promoting micro-milieu.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":27456015,"Year":2016,"Title":"MicroRNA Expression in a Readily Accessible Common Hepatic Artery Lymph Node Predicts Time to Pancreatic Cancer Recurrence Postresection.","Abstract":"Lymph node involvement in pancreatic adenocarcinoma (PAC) predicts postresection survival, but early lymph node metastasis detection is not easily accomplished. We assessed a panel of microRNAs (miRNAs) in a common hepatic artery lymph node (station 8) that is readily accessible during pancreatoduodenectomy (PD) to determine if increased miRNA levels correlate with postresection recurrence. Station 8 lymph nodes overlying the common hepatic artery collected during PD were assayed for miRNA-10b, miRNA-30c, miRNA-21, and miRNA-155 and cytokeratin-19 (CK19), an epithelial cell marker, using quantitative PCR. Expression was correlated with disease recurrence, recurrence-free survival (RFS), and overall survival (OS). Station 8 lymph nodes from 37 patients (30 periampullary carcinomas (PCs), 2 chronic pancreatitis, 5 other cancers) exhibited increased miRNA-10b levels in 14/30 PCs, and in 10 of these 14 patients, cancer recurred during the study period (2012-2015). High miRNA-10b was also associated with shorter RFS (42.5 vs. 92.4 weeks, p < 0.05) but not OS, whereas miRNA-30c, miRNA-21, and miRNA-155 levels and CK19 mRNA levels in station 8 nodes were variable and did not correlate with RFS or OS. We conclude that elevated miRNA-10b levels in station 8 lymph nodes could be utilized to assess risk for early disease progression in patients with periampullary tumors.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":27267055,"Year":2016,"Title":"Serum microRNA-196 and microRNA-200 in pancreatic ductal adenocarcinoma of patients with diabetes mellitus.","Abstract":"BACKGROUND/OBJECTIVES: Our aim was to compare expressions of 6 microRNAs (miRNAs) in patients with pancreatic ductal adenocarcinoma (PAC) and non-cancer patients, moreover according to the presence or absence of diabetes mellitus. METHODS: Expressions of miRNA-192, -196, -200, -21, -30 and -423 were measured in 77 patients with PAC and 64 non-cancer patients (34 patients with type 2 DM and 30 control persons). 60 patients with PAC (78%) had DM or prediabetes and it was of new-onset (less than 2 years before the cancer diagnosis) in 44 out of them. RESULTS: The expressions of all microRNAs were 1.4-3.7 times higher (significantly) in the PAC group compared to non-cancer patients. No difference was found between PAC diabetic and PAC non-diabetic patients. MicroRNA-200 was significantly higher in PAC patients with significant body weight loss against those without weight loss. Adding miRNA-196 and -200 to the current marker CA 19-9 improved the discriminative ability of the test (compared to CA 19-9 alone). CONCLUSION: MicroRNA-196 and -200 could be used as additional markers in PAC diagnosis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":27086919,"Year":2016,"Title":"Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies.","Abstract":"BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Novel biomarkers are required to aid treatment decisions and improve patient outcomes. MicroRNAs (miRNAs) are potentially ideal diagnostic biomarkers, as they are stable molecules, and tumour and tissue specific. RESULTS: Logistic regression analysis revealed an endoscopic-ultrasound fine-needle aspiration (EUS-FNA) 2-miRNA classifier (miR-21 + miR-155) capable of distinguishing benign from malignant pancreatic lesions with a sensitivity of 81.5% and a specificity of 85.7% (AUC 0.930). Validation FNA cohorts confirmed both miRNAs were overexpressed in malignant disease, while circulating miRNAs performed poorly. METHODS: Fifty-five patients with a suspicious pancreatic lesion on cross-sectional imaging were evaluated by EUS-FNA. At echo-endoscopy, the first part of the FNA was sent for cytological assessment and the second part was used for total RNA extraction. Candidate miRNAs were selected after careful review of the literature and expression was quantified by qRT-PCR. Validation was performed on an independent cohort of EUS-FNAs, as well as formalin-fixed paraffin embedded (FFPE) and plasma samples. CONCLUSIONS: We provide further evidence for using miRNAs as diagnostic biomarkers for pancreatic malignancy. We demonstrate the feasibility of using fresh EUS-FNAs to establish miRNA-based signatures unique to pancreatic malignant transformation and the potential to enhance risk stratification and selection for surgery.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26998056,"Year":2016,"Title":"Circulating microRNA profile predicts disease progression in patients receiving second-line treatment of lapatinib and capecitabine for metastatic pancreatic cancer.","Abstract":"Patients exhibiting pancreatic cancer possess poor rates of survival. Therefore, the identification of a biomarker that can be measured non-invasively and be used to predict patient outcomes is required for the successful treatment of pancreatic cancer. The present study evaluated serum microRNA (miRNA/miR) profiles in patients exhibiting pancreatic cancer, who were treated with lapatinib and capecitabine in a phase II trial. Serum samples were collected for the measurement of a panel of miRNAs (miR-21, miR-210, miR-221 and miR-7) associated with the epidermal growth factor receptor (EGFR)1 and human epidermal growth factor receptor (HER)2 pathways. Preclinically, human pancreatic cancer PANC-1, MIA PaCa-2 and BXCP-3 cell lines were utilized for miRNA and drug resistance studies. In total, 6/17 patients treated experienced disease progression following 2 cycles of treatment [non-responders (NRS)], while another 6/17 patients exhibited a stable disease state and received >4 cycles of treatment [responders (RS); range, 4-22 cycles]. Five patients withdrew from the study due to severe toxicity or mortality. The mean overall survival time was 6.5 vs. 10.4 months for NRS and RS, respectively. Significant upregulation of serum miRNAs at earlier time points (3-6 weeks) was observed in NRS. miRNA levels increased with cancer progression, and lapatinib and 5-fluorouracil (5-FU; the active form of capecitabine) treatment increased the miRNA levels (specifically miR-210 and miR-221) in the treatment-resistant pancreatic cancer PANC-1 and MIA PaCa-2 cell lines. However, lapatinib and 5-FU treatment did not increase the miRNA levels in the treatment-sensitive BXPC-3 cell line. Inhibition of miR-221 increased the sensitivity of the PANC-1 cells to treatment. In conclusion, an increase in specific serum miRNAs was associated with resistance to lapatinib and capecitabine treatment. Additional investigation is required with regard to the application of the miRNA panel investigated in the present study as a potential predictor of patient responses to anti-EGFR/HER2 treatment.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26977002,"Year":2016,"Title":"Locked Nucleic Acid In Situ Hybridization Analysis of MicroRNA-21 Predicts Clinical Outcome in Patients After Resection for Pancreatic Cancer Treated with Adjuvant Gemcitabine Monotherapy.","Abstract":"BACKGROUND: The overexpression of microRNA-21 (miR-21) in pancreatic cancer has been implicated in drug resistance to gemcitabine. Thus far, miR-21 has gained wide attention as a potential biomarker to predict the clinical response in patients with pancreatic cancer receiving gemcitabine. The aim of this study was to evaluate the predictive value of miR-21 expression, determined by locked nucleic acid in situ hybridization (LNA-ISH), in patients with pancreatic cancer who underwent adjuvant gemcitabine after curative surgery. MATERIALS AND METHODS: Tumor miR-21 expression was analyzed via LNA-ISH and correlated with the clinical outcomes of the patients treated with adjuvant gemcitabine. RESULTS: The overexpression of miR-21 in pancreatic cancer, determined by LNA-ISH, was significantly and independently associated with a shorter disease-free survival in patients who received adjuvant gemcitabine after curative resection. CONCLUSION: The LNA-ISH analysis of miR-21 may serve as a significant predictor for gemcitabine resistance in patients with pancreatic cancer undergoing adjuvant gemcitabine after curative resection.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26969625,"Year":2016,"Title":"Prognostic value of microRNA-21 in pancreatic ductal adenocarcinoma: a meta-analysis.","Abstract":"BACKGROUND: Recently, microRNA-21 (miR-21) has been reported to be associated with prognosis of pancreatic ductal adenocarcinoma (PDAC). The present studies aimed to evaluate the prognostic value of miR-21 for PDAC with meta-analysis. METHODS: A systematic search in the PubMed and other databases was conducted to identify eligible studies. The pooled hazard ratios (HRs) with 95% confidence interval (CI) were calculated. The meta-analysis was conducted using the STATA 12.0 software. RESULTS: A total of 12 articles (13 studies) which included 963 cases were selected for the meta-analysis. Elevated miR-21 expression was significantly predictive of poor overall survival (HR = 2.05, 95% CI 1.71-2.46, P < 0.001). In the subgroup analyses, similar results were observed in Asian (HR = 2.09, 95% CI 1.62-2.71, P < 0.001) and Caucasian (HR = 2.36, 95% CI 1.53-3.65, P < 0.001); in tissue sample (HR = 2.14, 95% CI 1.73-2.65, P < 0.001) and serum sample (HR = 1.84, 95% CI 1.30-2.60, P = 0.001); with quantitative real-time polymerase chain reaction assay method (HR = 2.31, 95% CI 1.86-2.86, P < 0.001); and in patients receiving adjuvant chemotherapy (HR = 2.37, 95% CI 1.88-3.00, P < 0.001). The association between miR-21 expression level and lymph node metastasis was statistically significant (OR = 1.45, 95% CI 1.02-2.06, P = 0.038). However, no significant relationship between miR-21 expression level and sex or vascular invasion or neural infiltration was observed (P > 0.05). CONCLUSIONS: Our meta-analysis indicated that elevated miR-21 expression level can predict poor prognosis in patients with PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26954494,"Year":2016,"Title":"Support Vector Machine Based on microRNA Expression Profiles to Predict Histological Origin of Ampullary Carcinoma: Case Report of a Patient Affected From Adenocarcinoma of the Papilla of Vater With Lynch Syndrome.","Abstract":"Adenocarcinomas of Vater's papilla (PVAC) may originate from either the pancreatic duct or the intestinal epithelium. Conflicting data have been reported about the frequency of the 2 anatomical entities and their influence on patients' prognosis. To ascertain the anatomical origin of PVAC in a family member of a Lynch syndrome kindred, we searched for microRNA (miRNA) expression profiles on resected tumor specimens. The support vector machine was trained on our previous miRNAs expression data sets of pancreatic and colorectal tissue samples and used to classify the site of origin of the tumor in our patient. The support vector machine worked by contrasting the profiles of miRNAs in patients with pancreatic ductal and colorectal cancers to that of our patient, which was finally classified as pancreatic ductal adenocarcinoma accordingly to alterations of 55 miRNAs. The PVAC might be originated from ductal epithelium rather than from the intestinal mucosa of the papilla in the case at issue. Alteration of miR-548b-3p, miR-551a, miR-21, miR-92a, miR-let-7i, and miR-181a* emerged as potentially associated with cancer genetic susceptibility in PVAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26864640,"Year":2016,"Title":"MicroRNA-21 induces 5-fluorouracil resistance in human pancreatic cancer cells by regulating PTEN and PDCD4.","Abstract":"Pancreatic cancer patients are often resistant to chemotherapy treatment, which results in poor prognosis. The objective of this study was to delineate the mechanism by which miR-21 induces drug resistance to 5-fluorouracil (5-FU) in human pancreatic cancer cells (PATU8988 and PANC-1). We report that PATU8988 cells resistant to 5-FU express high levels of miR-21 in comparison to sensitive primary PATU8988 cells. Suppression of miR-21 expression in 5-Fu-resistant PATU8988 cells can alleviate its 5-FU resistance. Meanwhile, lentiviral vector-mediated overexpression of miR-21 not only conferred resistance to 5-FU but also promoted proliferation, migration, and invasion of PATU8988 and PANC-1 cells. The proresistance effects of miR-21 were attributed to the attenuated expression of tumor suppressor genes, including PTEN and PDCD4. Overexpression of PTEN and PDCD4 antagonized miR-21-induced resistance to 5-FU and migration activity. Our work demonstrates that miR-21 can confer drug resistance to 5-FU in pancreatic cancer cells by regulating the expression of tumor suppressor genes, as the target genes of miR-21, PTEN and PDCD4 can rescue 5-FU sensitivity and the phenotypic characteristics disrupted by miR-21.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26862857,"Year":2016,"Title":"miR-21 expression and clinical outcome in locally advanced pancreatic cancer: exploratory analysis of the pancreatic cancer Erbitux, radiotherapy and UFT (PERU) trial.","Abstract":"BACKGROUND: Locally advanced pancreatic cancer (LAPC) is associated with high mortality, and biomarker-driven treatment approach is currently lacking. This study evaluated safety and efficacy of a combination approach of chemotherapy followed by chemo-radiotherapy (CRT) +/- cetuximab, and the prognostic role of miR-21 in patients with LAPC treated with a multimodality approach. PATIENTS AND METHODS: This was a randomised phase II trial in which patients with inoperable LAPC were offered gemcitabine and capecitabine (GEM-CAP) for 16 weeks. Patients with stable disease or response after GEM-CAP were randomised to capecitabine or UFT plus radiotherapy (RT) (A), or capecitabine or UFT plus cetuximab plus RT (B). The primary outcome of the study was overall survival (OS). Clinical outcome was compared according to baseline circulating miR-21 levels. RESULTS: 17 patients were enrolled and treated with GEM-CAP, with 13 patients achieving disease control and being randomised to arms A (n:7) and B (n:6). After a median follow-up of 61.2 months, median progression free survival (PFS) was 10.4 months and 12.7 months, median OS was 15.8 months and 22.0 months in arms A and B respectively (p > 0.05). Patients with high baseline plasma miR-21 had worse PFS (3.5 vs. 12.7 months; p:0.032) and OS (5.1 vs 15.3 months; p:0.5) compared to patients with low miR-21. Circulating miR-21 levels reflected miR-21 expression within the tissues. CONCLUSIONS: Addition of Cetuximab to CRT following induction chemotherapy did not improve survival. High miR-21 baseline plasma expression was associated with poor clinical outcome in LAPC patients treated with induction chemotherapy followed by chemo-radiotherapy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26819679,"Year":2015,"Title":"Differential Expression of MicroRNAs in Tissues and Plasma Co-exists as a Biomarker for Pancreatic Cancer.","Abstract":"OBJECTIVE: Pancreatic cancer (PC) is a lethal disease with disappointing results from current treatment modalities, suggesting that novel therapeutic strategies are urgently needed. Since microRNAs (miRNAs) are important player in biology, the clinical utility of miRNAs for designing novel therapeutics is an active area of research. The objective of the present study was to examine differentially expressed miRNAs between normal and tumor tissues, and in plasma samples obtained from PC patients, chronic pancreatitis (CP) patients and healthy subjects (HC). MATERIAL AND METHODS: The miRNA expression profiling using formalin-fixed paraffin embedded (FFPE) tissues from normal and tumor specimens was accomplished using miRBase version 19 (LC Sciences, Houston, TX, USA). Quantitative real-time PCR (qRT-PCR) was subsequently performed in individual samples for 7 selected miRNAs. In addition, qRT-PCR was also performed for assessing the expression of 8 selected miRNAs in plasma samples. RESULTS: A significant difference in the expressions of miR-21, miR-205, miR-155, miR-31, miR-203, miR-214 and miR-129-2 were found in tumor tissue samples. Lower expression of miR-214 was found to be associated with better overall survival. We also observed differential expression of 8 miRNAs in plasma samples of CP and PC patients compared to HC. Interestingly, over expression of miR-21, and miR-31 was noted in both tumor tissues and in the plasma. CONCLUSION: We found deregulated expression of miRNAs that could distinguish normal from PC in two different types of samples (tissues and plasma). Interestingly, lower expression of miR-214 was found to be associated with better overall survival. Although not statistically significant, we also observed higher expression of let-7a and lower expression of miR-508 to be associated with overall better survival. We conclude that our study nicely lays the foundation for detailed future investigations for assessing the role of these miRNAs in the pathology of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26705427,"Year":2015,"Title":"MicroRNA-100 and microRNA-21 as markers of survival and chemotherapy response in pancreatic ductal adenocarcinoma UICC stage II.","Abstract":"BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a highly chemoresistant tumor entity for which no reliable molecular targets exist to predict or influence the success of chemotherapy. Recently, we identified a panel of microRNAs associated with induced gemcitabine chemoresistance in human PDAC cell lines. This clinical study evaluates these microRNAs and associated molecular markers as prognostic markers of outcome in 98 PDAC patients Union Internationale Contre le Cancer (UICC) stage II undergoing curative surgery with adjuvant gemcitabine chemotherapy. The primary end points of this study are recurrence-free survival and overall survival. RESULTS: Poor response to chemotherapy was significantly correlated to overexpression of microRNA-21 (p = 0.029), microRNA-99a (p = 0.037), microRNA-100 (p = 0.028), and microRNA-210 (p = 0.021) in tissue samples of PDAC patients UICC stage II. Upregulation of these microRNAs was associated with a significantly shorter overall survival and recurrence-free survival (p < 0.05). Overexpression of phosphatase and tensin homolog (PTEN) (p = 0.039) and low expression of multidrug resistance (MDR)-1 (p = 0.043) and breast cancer resistance protein (BCRP)-1 (p = 0.038) were significantly correlated to improved response to adjuvant chemotherapy. Adjuvant gemcitabine treatment (p < 0.0001) and low tumor grading (p = 0.047) were correlated to better outcome. MicroRNA-100, microRNA-21, and its targets PTEN and MDR-1 were independent factors of survival in multivariate analysis. CONCLUSIONS: Multivariate survival analyses identified microRNA-21 and microRNA-100 as unfavorable prognostic factors in resected and adjuvant treated PDAC UICC stage II patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26606261,"Year":2015,"Title":"MicroRNA Profiling Implies New Markers of Gemcitabine Chemoresistance in Mutant p53 Pancreatic Ductal Adenocarcinoma.","Abstract":"BACKGROUND: No reliable predictors of susceptibility to gemcitabine chemotherapy exist in pancreatic ductal adenocarcinoma (PDAC). MicroRNAs (miR) are epigenetic gene regulators with tumorsuppressive or oncogenic roles in various carcinomas. This study assesses chemoresistant PDAC for its specific miR expression pattern. METHODS: Gemcitabine-resistant variants of two mutant p53 human PDAC cell lines were established. Survival rates were analyzed by cytotoxicity and apoptosis assays. Expression of 1733 human miRs was investigated by microarray and validated by qRT-PCR. After in-silico analysis of specific target genes and proteins of dysregulated miRs, expression of MRP-1, Bcl-2, mutant p53, and CDK1 was quantified by Western blot. RESULTS: Both established PDAC clones showed a significant resistance to gemcitabine (p<0.02) with low apoptosis rate (p<0.001) vs. parental cells. MiR-screening revealed significantly upregulated (miR-21, miR-99a, miR-100, miR-125b, miR-138, miR-210) and downregulated miRs (miR-31*, miR-330, miR-378) in chemoresistant PDAC (p<0.05). Bioinformatic analysis suggested involvement of these miRs in pathways controlling cell death and cycle. MRP-1 (p<0.02) and Bcl-2 (p<0.003) were significantly overexpressed in both resistant cell clones and mutant p53 (p = 0.023) in one clone. CONCLUSION: Consistent miR expression profiles, in part regulated by mutant TP53 gene, were identified in gemcitabine-resistant PDAC with significant MRP-1 and Bcl-2 overexpression. These results provide a basis for further elucidation of chemoresistance mechanisms and therapeutic approaches to overcome chemoresistance in PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26516699,"Year":2015,"Title":"Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model.","Abstract":"Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26499892,"Year":2015,"Title":"Small nucleolar RNA U91 is a new internal control for accurate microRNAs quantification in pancreatic cancer.","Abstract":"BACKGROUND: RT-qPCR quantification of miRNAs expression may play an essential role in pancreatic ductal adenocarcinoma (PDAC) diagnostics. RT-qPCR-based experiments require endogenous controls for the result normalization and reliability. However, expression instability of reference genes in tumors may introduce bias when determining miRNA levels. METHODS: We investigated expression of 6 miRNAs, isolated from FFPE samples of pancreatic adenocarcinomas. Four internal controls were utilized for RT-qPCR result normalization: artificial miR-39 from C. elegans, U6 snRNA, miR-16 and snoRNA U91. RESULTS: We found miR-21, miR-155 or miR-217 expression values in tumors may differ up to several times, depending on selected internal controls. Moreover, different internal controls can produce controversial results for miR-96, miR-148a or miR-196a quantification. Also, expression of our endogenous controls varied significantly in tumors. U6 demonstrated variation from -1.03 to 8.12-fold, miR-16 from -2.94 up to 7.38-fold and the U91 from -3.05 to 4.36-fold respectively. On the other hand, the most stable gene, determined by NormFinder algorithm, was U91. Each miRNA normalized relatively to the spike or U91, demonstrated similar expression values. Thus, statistically significant and insignificant differences between tumors and normal tissues for miRNAs were equal for the spike and the U91. Also, the differences between the spike and U91 were statistically insignificant for all of miRs except miR-217. Among three endogenous controls, U91 had the lowest average expression values and standard deviation in cancer tissues. CONCLUSIONS: We recommend U91 as a new normalizer for miRNA quantification in PDACs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26312859,"Year":2015,"Title":"Integrated molecular analysis to investigate the role of microRNAs in pancreatic tumour growth and progression.","Abstract":"BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs involved in the post-transcriptional regulation of mRNAs and are aberrantly expressed in cancer with important roles in tumorigenesis. A broad analysis of the combined effects of altered activities of miRNAs in pancreatic ductal adenocarcinoma (PDAC) has not been done, and how miRNAs might affect tumour progression or patient outcomes is unclear. METHODS: We combined data from miRNA and mRNA expression profiles from PDAC and normal pancreas samples (each n=9) and used bioinformatic analyses to identify a miRNA-mRNA regulatory network in PDAC. We validated our findings in PDAC cell-lines (PANC-1, MIA PaCa-2, LPc006, and LPc167), subcutaneous PDAC xenografts in mice, and laser capture microdissected PDACs from patients (n=91). We used this information to identify miRNAs that contributed most to tumorigenesis. FINDINGS: We identified three miRNAs (miR-21, miR-23a, and miR-27a) that acted as cooperative repressors of a network of tumour suppressor genes that included PDCD4, BTG2, and NEDD4L. Inhibition of miR-21, miR-23a, and miR-27a had synergistic effects in reducing proliferation of PDAC cells in culture and the growth of xenograft tumours. The level of inhibition was greater than that of silencing oncomiR-21 alone. In PDACs from patients, high levels of the combination of miR-21, miR-23a, and miR-27a was a strong independent predictor of short overall survival after surgical resection (hazard ratio 3.21, 95% CI 1.78-5.78). High expression of this combination was also associated with a more aggressive tumour phenotype: more microscopic tumour infiltration at resection margin and increased perineural invasion. INTERPRETATION: In an integrated data analysis, we identified functional miRNA-mRNA interactions that contribute to PDAC growth. These findings indicate that miRNAs act together to promote tumour progression and that future therapeutic strategies might require inhibition of several miRNAs. Furthermore, high tumour expression of the miR-21, miR-23a, and miR-27a combination could have potential use in the future as a prognostic signature for patients with PDAC. FUNDING: Peel Medical Research Trust, Alliance Family Foundation, Action Against Cancer, National Institute for Health Research, Association for International Cancer Research, Jason Boas Fellowship, Imperial Biomedical Research Centre, Rosetrees Trust, Joseph Ettedgui Charitable Foundation.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26284487,"Year":2015,"Title":"Simultaneous inhibition of multiple oncogenic miRNAs by a multi-potent microRNA sponge.","Abstract":"The roles of oncogenic miRNAs are widely recognized in many cancers. Inhibition of single miRNA using antagomiR can efficiently knock-down a specific miRNA. However, the effect is transient and often results in subtle phenotype, as there are other miRNAs contribute to tumorigenesis. Here we report a multi-potent miRNA sponge inhibiting multiple miRNAs simultaneously. As a model system, we targeted miR-21, miR-155 and miR-221/222, known as oncogenic miRNAs in multiple tumors including breast and pancreatic cancers. To achieve efficient knockdown, we generated perfect and bulged-matched miRNA binding sites (MBS) and introduced multiple copies of MBS, ranging from one to five, in the multi-potent miRNA sponge. Luciferase reporter assay showed the multi-potent miRNA sponge efficiently inhibited 4 miRNAs in breast and pancreatic cancer cells. Furthermore, a stable and inducible version of the multi-potent miRNA sponge cell line showed the miRNA sponge efficiently reduces the level of 4 target miRNAs and increase target protein level of these oncogenic miRNAs. Finally, we showed the miRNA sponge sensitize cells to cancer drug and attenuate cell migratory activity. Altogether, our study demonstrates the multi-potent miRNA sponge is a useful tool to examine the functional impact of simultaneous inhibition of multiple miRNAs and proposes a therapeutic potential.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26264831,"Year":2015,"Title":"Polyethylenimine-coated SPION exhibits potential intrinsic anti-metastatic properties inhibiting migration and invasion of pancreatic tumor cells.","Abstract":"Due to its aggressive behavior, pancreatic cancer is one of the principal causes of cancer-related deaths. The highly metastatic potential of pancreatic tumor cells demands the development of more effective anti-metastatic approaches for this disease. Although polyethylenimine-coated superparamagnetic iron oxide nanoparticles (PEI-coated SPIONs) have been studied for their utility as transfection agents, little is known of their effect on tumor cell biology. Here we demonstrated that PEI-coated SPIONs have potent inhibitory effects on pancreatic tumor cell migration/invasion, through inhibition of Src kinase and decreased expression of MT1-MMP and MMP2 metalloproteinases. When treated with PEI-coated SPIONs, the pancreatic tumor cell line Pan02 showed reduced invadosome density and thus, a decrease in their ability to invade through basement membrane. These nanoparticles temporarily downmodulated microRNA-21, thereby upregulating the cell migration inhibitors PTEN, PDCD4 and Sprouty-1. PEI-coated SPIONs thus show intrinsic, possibly anti-metastatic properties for modulating pancreatic tumor cell migration machinery, which indicates their potential as anti-metastatic agents for treatment of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26262588,"Year":2016,"Title":"miRNA-21 and miRNA-34a Are Potential Minimally Invasive Biomarkers for the Diagnosis of Pancreatic Ductal Adenocarcinoma.","Abstract":"OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly cancers, and its diagnosis often requires invasive procedures. Deregulated miRNA expression has been described in patients with PDAC. In this study, we analyzed the expression levels of 6 miRNAs (miR-21, -34a, -155, -196a, -200b, and -376a involved in PDAC tumorigenesis) in serum and salivary samples to assess their potential role as circulating diagnostics biomarkers. METHODS: Serum and salivary samples were collected from patients with PDAC and healthy controls, and miRNA levels were quantified using qRT-PCR. Twenty-four patients with PDAC and 10 healthy controls were recruited. RESULTS: A significant difference between PDAC and healthy groups was observed for the expression of miR-21 and miR-34a (P < 0.001 and P = 0.001) in serum samples. Both miRNAs accurately discriminated between the 2 groups, with an area under the curve for miR-21 and miR-34a of 0.889 (P = 0.001) and 0.865 (P = 0.002), respectively. In general, the expression of miRNAs between salivary samples did not differ. CONCLUSIONS: Serum miR-21 and miR-34a are potentially useful diagnostic biomarkers of PDAC. In addition, our results suggest that these miRNAs are not differentially expressed in saliva, making them unsuitable for use as noninvasive biomarkers for diagnostic purposes.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26250566,"Year":2016,"Title":"Circulating U2 small nuclear RNA fragments as a novel diagnostic biomarker for primary central nervous system lymphoma.","Abstract":"BACKGROUND: Primary central nervous system lymphomas (PCNSLs) are highly aggressive tumors. Chemotherapy has improved prognosis significantly; however, early diagnosis is crucial for effective treatment. Presently, the diagnosis of PCNSL depends on histopathology of tumor biopsies. We have previously demonstrated differential expression of microRNAs in cerebrospinal fluid (CSF) samples from patients with PCNSL. Based on promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic, colorectal, and lung cancer, we investigated RNU2-1f in the CSF of PCNSL patients. METHODS: CSF was collected from patients with PCNSL (n = 72) and control patients with various neurologic disorders (n = 47). Sequential CSF samples were collected from 9 PCNSL patients. RNU2-1f levels were measured by real-time polymerase chain reaction. RESULTS: Measurement of RNU2-1f levels in CSF enabled the differentiation of patients with PCNSL from controls with an area under the curve (AUC) of 0.909 with a sensitivity of 68.1% and a specificity of 91.4%. The diagnostic accuracy was further improved by combined determination of RNU2-1f and miR-21, resulting in AUC of 0.987 with a sensitivity of 91.7% and a specificity of 95.7%. In consecutive measurements of RNU2-1f, which were performed in 9 patients at different stages of the disease course, RNU2-1f CSF levels paralleled the course of the disease. CONCLUSIONS: Our data suggest that the measurement of RNU2-1f detected in CSF can be used as a diagnostic marker and also as a possible marker for treatment monitoring. These promising results need to be evaluated within a larger patient cohort.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26210448,"Year":2015,"Title":"MiR-21 promoted proliferation and migration in hepatocellular carcinoma through negative regulation of Navigator-3.","Abstract":"MicroRNA-21 (miR-21) has been well-established and found to be over-expressed in various human cancers and has been associated with hepatocellular carcinoma (HCC) progression. However, the underlying mechanism of miR-21 involvement in the development and progression of HCC remains to be understood. In the present study, we firstly identified that the Navigator-3 (NAV-3) gene as a novel direct target of miR-21. Knock-down of NAV-3 using shRNA can rescue the effects of anti-miR-21 inhibitor in HCC cell lines, whereas re-expression of miR-21 using transfection with miR-21 mimics phenocopied the NAV-3 knock-down model. Additionally, miR-21 levels inversely correlated with NAV-3 both in HCC cells and tissues. Knock-down of NAV-3 promoted both the proliferation and migration in HCC cells. Together, our findings suggest an important role for miR-21 in the progression of HCC, which negatively regulated Navigator-3 in the migration of HCC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26121640,"Year":2015,"Title":"Salivary MicroRNA in Pancreatic Cancer Patients.","Abstract":"BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in Western countries, with the lowest 1-year survival rate among commonly diagnosed cancers. Reliable biomarkers for pancreatic cancer diagnosis are lacking and are urgently needed to allow for curative surgery. As microRNA (miRNA) recently emerged as candidate biomarkers for this disease, we explored in the present pilot study the differences in salivary microRNA profiles between patients with pancreatic tumors that are not eligible for surgery, precancerous lesions, inflammatory disease or cancer-free patients as a potential early diagnostic tool. METHODS: Whole saliva samples from patients with pancreatic cancer (n = 7), pancreatitis (n = 4), IPMN (n = 2), or healthy controls (n = 4) were obtained during endoscopic examination. After total RNA isolation, expression of 94 candidate miRNAs was screened by q(RT)PCR using Biomark Fluidgm. Human-derived pancreatic cancer cells were xenografted in athymic mice as an experimental model of pancreatic cancer. RESULTS: We identified hsa-miR-21, hsa-miR-23a, hsa-miR-23b and miR-29c as being significantly upregulated in saliva of pancreatic cancer patients compared to control, showing sensitivities of 71.4%, 85.7%, 85,7% and 57%, respectively and excellent specificity (100%). Interestingly, hsa-miR-23a and hsa-miR23b are overexpressed in the saliva of patients with pancreatic cancer precursor lesions. We found that hsa-miR-210 and let-7c are overexpressed in the saliva of patients with pancreatitis as compared to the control group, with sensitivity of 100% and 75%, and specificity of 100% and 80%, respectively. Last hsa-miR-216 was upregulated in cancer patients as compared to patients diagnosed with pancreatitis, with sensitivity of 50% and specificity of 100%. In experimental models of PDAC, salivary microRNA detection precedes systemic detection of cancer cells markers. CONCLUSIONS: Our novel findings indicate that salivary miRNA are discriminatory in pancreatic cancer patients that are not eligible for surgery. In addition, we demonstrate in experimental models that salivary miRNA detection precedes systemic detection of cancer cells markers. This study stems for the use of salivary miRNA as biomarker for the early diagnosis of patients with unresectable pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26068418,"Year":2015,"Title":"FoxO1-negative cells are cancer stem-like cells in pancreatic ductal adenocarcinoma.","Abstract":"Flow cytometry assays using aldehyde dehydrogenase (ALDH) activity or CD133 positivity to isolate cancer stem cells (CSCs) are widely applied but have limitations. Thus, characterization of CSC makers for a specific cancer is potentially important. We have previously shown that miR-21 regulates cancer cell growth via FoxO1 in pancreatic ductal adenocarcinoma (PDAC). Here, we areported evidence of FoxO1-negative PDAC cells as CSCs in PDAC. Both ALDH-high and CD133-high cell fractions isolated from PDAC of the patients expressed high levels of miR-21 and null FoxO1. Cultured PDAC cells were virally transduced with GFP under FoxO1 promoter. GFP (FoxO1)-null PDAC cells expressed high levels of miR-21, and grew more quickly than FoxO1-positive PDAC cells. Moreover, the fold increases in growth of FoxO1-negative vs FoxO1-positive cells were greater than CD133-high vs CD133-low cells, or ALDH-high vs ALDH-low cells. Further, FoxO1-negative cells formed tumor spheres in culture and developed tumors after serial adoptive transplantation into NOD/SCID mice, while the FoxO1-positive cells did not. Finally, selective elimination of FoxO1-negative cells completely inhibited the growth of PDAC cells. Together, these data suggest that FoxO1-negative cells as CSCs in PDAC, and targeting FoxO1-negative cells in PDAC may provide better therapeutic outcome.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":26046003,"Year":2015,"Title":"Contribution of microRNAs in understanding the pancreatic tumor microenvironment involving cancer associated stellate and fibroblast cells.","Abstract":"Understanding of molecular events associated with tumor microenvironment in pancreatic cancer (PC) is an active area of research especially because of the rich desmoplasia seen in human PC. Desmoplasia is contributed by several cell types including cancer-associated fibroblast (CAF) and stellate cells (PSCs), which are believed to play critical roles in conferring aggressiveness to PC. The aberrant expression of microRNAs (miRNAs) in PSCs and CAF cells appears to play a pivotal role in the development and progression of PC. In this study, expression analysis of miR-21/miR-221 in conditioned media derived from PSCs/CAF cells, and from PSCs/CAF cells showed up-regulation of both miRNAs compared to MIAPaCa-2 PC cells. In addition, miR-21 expression in stellate cells derived from normal pancreas was substantially lower when compared to PSCs or CAF cells. COLO-357 PC cells cultured in the presence of conditioned media derived from PSC/CAF cells led to a significant increase in clonogenicity and pancreatosphere formation. Furthermore, inhibition of miR-21 with antisense oligonucleotide (ASO) transfection resulted in decreased migration/invasive capacity of PSCs. Similarly, the effect of ASO-miR-221 transfection in CAF cells reduced the expression of NF-kappaB and K-Ras (target of miR-221) along with inhibition of migration/invasion. Moreover, miRNA expression profiling of PSCs, MIAPaCa-2, and COLO-357 cells, and further validation by real-time PCR, showed several differentially expressed miRNAs, among which four was significantly up-regulated. Collectively, these results suggest a crosstalk between PSCs/CAF cells and PC cells, resulting in the up-regulation of miR-21/miR-221 expression which in part may confer aggressiveness to PC. We conclude that targeting these miRNAs could be useful for developing precision medicine for the prevention of tumor progression and/or for the treatment of PC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25908274,"Year":2015,"Title":"MiR-21, miR-34a, miR-198 and miR-217 as diagnostic and prognostic biomarkers for chronic pancreatitis and pancreatic ductal adenocarcinoma.","Abstract":"BACKGROUND: Pancreatic ductal adenocarcinoma is an aggressive malignancy with late presentation, metastatic potential and very poor prognosis. Therefore, there is an urgent need for novel diagnostic and prognostic biomarkers. MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. Altered expression of microRNAs has been reported in wide range of malignancies, including pancreatic ductal adenocarcinoma. The aim of this study was to analyze the expression of selected microRNAs in normal pancreas, chronic pancreatitis and pancreatic ductal adenocarcinoma tissues and evaluate their diagnostic and prognostic potential. FINDINGS: Using quantitative real-time PCR, expression levels of 4 microRNAs were examined in 74 tumor tissues, 18 tissues of chronic pancreatitis and 9 adjacent normal tissues and correlated with clinicopathological features of patients. Expression levels of miR-21, miR-34a and miR-198 were significantly higher, whereas levels of miR-217 were significantly lower in pancreatic ductal adenocarcinomas compared to healthy tissues and tissues of chronic pancreatitis. Moreover, increased expression of miR-21 and miR-198 was significantly associated with shorter disease free survival and overall survival. CONCLUSIONS: Our data suggest that altered expression of examined microRNAs is related to neoplastic transformation and progression of the disease and these microRNAs could serve as diagnostic and prognostic biomarkers for pancreatic ductal adenocarcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1373952531543898.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25894267,"Year":2015,"Title":"[miRNA-192, miRNA-21 and miRNA-200: new pancreatic cancer markers in diabetic patients?].","Abstract":"INTRODUCTION: Newly-onset diabetes mellitus (DM) in middle-aged and older people may be an early symptom of pancreatic cancer (PC). However, sensitive markers for PC are still missing. MicroRNAs (miRNAs) play an important role in a cell response regulation. Significant changes in miRNA expressions were observed in cancers. Our goal was to compare expressions of selected miRNAs in patients with PC, DM and controls. METHODS: We enrolled 74 patients with PC (42/32, with/without DM), 29 type 2 diabetic patients and 17 controls. MicroRNA was determined in serum of all examined subjects. In 9 patients with PC the tumor was resected subsequently and after 3 months the measurements were repeated. We analyzed the expressions of 8 miRNAs that we had identified in a previous pilot study (miR-21, miR-30, miR-191, miR-192, miR-196, miR-200, miR-423, miR-454). RESULTS: MicroRNA expressions were significantly higher in patients with PC than in DM and controls: miR-192: 1.6 (1.2 to 2.0) vs 0.3 (0.2-0.4) vs 0.3 (0.2 to 0.5), p < 0.00001; miR-21: 1.4 (1.2-1.7) vs 0.3 (0.2 to 0.5) vs 0.5 (from 0.4 to 0.7), p < 0.00001, miR-200: 1.6 (1.1 to 2.3) vs 0.3 (0.3-0.4) vs 0.3 (0.2 to 0.4), p < 0.00001. No difference was observed between DM and controls, as well as between diabetic and non-diabetic patients within the PC group. There were no significant differences in miRNA expressions in 9 patients after pancreatic surgery. But there were significant interindividual differences. CONCLUSION: Our data shows that miR-21, miR-192 and miR-200 could be used as new diagnostic markers for pancreatic cancer. A dynamics of these miRNAs could serve as a prognostic marker in patients after cancer removal. Futher prospective studies with newly-onset diabetic patients with no signs of malignancy will be needed to validate if suggested miRNAs could be used as early markers as well.","Language":"cze","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25846727,"Year":2015,"Title":"p85alpha is a microRNA target and affects chemosensitivity in pancreatic cancer.","Abstract":"BACKGROUND: We previously identified a correlation between increased expression of the phosphoinositide 3-kinase (PI3K) regulatory subunit p85alpha and improved survival in human pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to investigate the impact of changes in p85alpha expression on response to chemotherapy and the regulation of p85alpha by microRNA-21 (miR-21). MATERIALS AND METHODS: PDAC tumor cells overexpressing p85alpha were generated by viral transduction, and the effect of p85alpha overexpression on sensitivity to gemcitabine was tested by MTT assay. Primary human PDAC tumors were stained for p85alpha and miR-21 via immunohistochemistry and in situ hybridization, respectively. Additionally, PDAC cells were treated with miR-21 mimic, and changes in p85alpha and phospho-AKT were assessed by Western blot. Finally, a luciferase reporter assay system was used to test direct regulation of p85alpha by miR-21. RESULTS: Higher p85alpha expression resulted in increased sensitivity to gemcitabine (P < 0.01), which correlated with decreased PI3K-AKT activation. Human tumors demonstrated an inverse correlation between miR-21 and p85alpha expression levels (r = -0.353, P < 0.001). In vitro, overexpression of miR-21 resulted in decreased levels of p85alpha and increased phosphorylation of AKT. Luciferase reporter assays confirmed the direct regulation of p85alpha by miR-21 (P < 0.01). CONCLUSIONS: Our results demonstrate that p85alpha expression is a determinant of chemosensitivity in PDAC. Additionally, we provide novel evidence that miR-21 can influence PI3K-AKT signaling via its direct regulation of p85alpha. These data provide insight into potential mechanisms for the known relationship between increased p85alpha expression and improved survival in PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25639539,"Year":2015,"Title":"Antisense inhibition of microRNA-21 and microRNA-221 in tumor-initiating stem-like cells modulates tumorigenesis, metastasis, and chemotherapy resistance in pancreatic cancer.","Abstract":"Our preliminary studies identified a small population side population (SP) cells in pancreatic cancer cells with stem cell-like properties, which were able to induce fast and aggressive tumor formation in nude mice. Gene expression analysis showed a significant difference in the expression of more than 1,300 genes in SP cells, among which a highly significant difference in microRNA expression of miR-21 and miR-221 between SP and NSP cells was identified. SP cells were identified and characterized by flow cytometry using Hoechst 33342 dye staining from a highly metastatic human pancreatic cancer cell line (L3.6pl). Antagomir transfection was performed using miRNA-21 and miRNA-221 antisense oligonucleotides (ASOs) and followed by detection of cell apoptosis, cell cycle progression, chemosensitivity, and invasion. Sorted SP cells from gemcitabine-resistant L3.6pl cells (L3.6pl(Gres)-SP) cells were orthotopically implanted in nude mice with or without miRNA-21 and miRNA-221 ASOs mono- and combination therapy. The administration of antagomir-21 and antagomir-221 significantly reduced the SP cell fraction, decreased SP cell differentiation, and downstream gene regulation, and thereby induced reduction of L3.6pl cell proliferation, invasion, and chemoresistance against gemcitabine and 5-Fluorouracil. Combination of ASOs therapy against miRNA-21 and miRNA-221 significantly inhibited primary tumor growth and metastasis compared to single antagomir treatment, especially, in L3.6plGres-SP-induced pancreatic tumor growth in vivo. These findings further indicate that the inhibition of miR-21 and miR-221 appear particularly suitable to target stem-like subpopulations and address their specific biological function to promote tumor progression in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25623117,"Year":2015,"Title":"Interplay of miR-21 and FoxO1 modulates growth of pancreatic ductal adenocarcinoma.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant primary tumors in humans, with extremely high lethality. Although great efforts have been made to understand the molecular regulation of the tumorigenesis of PDAC, our current knowledge remains very limited. Previous work has shown a possible involvement of miR-21 in the growth of PDAC, whereas the underlying mechanism has not been clarified. Here, we show significant higher levels of miR-21 in PDAC, compared to the adjacent normal pancreatic tissue. Moreover, overexpression of miR-21 in PDAC cells increased cell growth, whereas inhibition of miR-21 decreased cell growth. Furthermore, miR-21 was found to inhibit nuclear retention of FoxO1 to augment the growth of PDAC cells. Thus, miR-21/FoxO1 axis appears to be a novel therapeutic target for inhibiting the growth of PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25591761,"Year":2015,"Title":"Modulation of FoxO1 expression by miR-21 to promote growth of pancreatic ductal adenocarcinoma.","Abstract":"BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal primary tumors in humans, with undetermined tumorigenesis. Although previous work by us, and by others, has clearly demonstrated an involvement of miR-21 in the growth of PDAC, the underlying mechanism has not been clarified. METHODS: Here we analyzed the regulation of FoxO1 by miR-21 in vitro and in vivo, using luciferase-reporter assay and pancreatic intraductal infusion of antisense of miR-21, respectively. RESULTS: We found that overexpression of miR-21 in PDAC cells decreased FoxO1 protein levels, whereas inhibition of miR-21 increased FoxO1 levels. Further, miR-21 bound to FoxO1 mRNA to prevent its translation through its 3'UTR. Moreover, administration of antisense of miR-21 through an intraductal infusion system significantly decreased miR-21 levels and increased FoxO1 levels in implanted PDAC, resulting in a significant decrease in PDAC growth. CONCLUSION: Taken together, our data highlight miR-21/FoxO1 axis as a novel therapeutic target for inhibiting the growth of PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25520858,"Year":2014,"Title":"MicroRNAs in stool samples as potential screening biomarkers for pancreatic ductal adenocarcinoma cancer.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90-95% exocrine malignant tumors of the pancreas. The high prevalence of metastasis and the difficulty of early diagnosis lead to a dismal prognosis. MicroRNAs (miRNAs) play a critical role in extensive biological processes. The purpose of this study was to evaluate the feasibility of stool miRNAs as novel biomarker for PDAC screening. MiRNAs were extracted from clinical specimens which included cancer and matched adjacent benign pancreatic tissues of 30 PDAC patients, pancreatic juice of 20 from the 30 PDAC patients and 10 chronic pancreatitis (CP) patients, stool samples of the 30 PDAC patients, the 10 CP patients and 15 healthy volunteers. Relative expression of a panel of 5 dysregulated miRNAs (miR-21, miR-155, miR-196a, miR-216 and miR-217) was analyzed with qRT-PCR. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool miRNAs in PDAC patients. The study showed that our methods of extracting and detecting miRNAs from pancreatic juice and stool specimens had high reproducibility. Compared to matched adjacent benign pancreatic tissues and pancreatic juice of CP patients, the expression of miR-21 (P = 0.0021 and P = 0.0027) as well as miR-155 (P = 0.0087 and P = 0.0067) was significantly higher and the expression of miR-216 (P < 0.0001 and P = 0.0044) was significantly lower in primary tumor tissues and pancreatic juice of PDAC patients. PDAC patients had a significantly higher stool miR-21 and miR-155 (P = 0.0049 and P = 0.0112) and lower miR-216 level (P = 0.0002) compared to normal controls. The same results were obtained in the expression levels of stool miR-21, miR-155 and miR-216 between PDAC and CP patients (P = 0.0337, P = 0.0388 and P = 0.0117, respectively). Receiver operating characteristic (ROC) analysis by using stool miRNAs expression indicated that combination of miR-21 and miR-155 had best sensitivity of 93.33% while the combination of miR-21, miR-155 and miR-216 would be best for detecting and screening PDAC with area under the curve (AUC) of 0.8667 (95% CI: 0.7722-0.9612) and a better balance of sensitivity and specificity (83.33% vs. 83.33%). Our data indicate that miRNAs could be extracted and detected from pancreatic juice and stool efficiently and reproducibly. MiR-21, miR-155 and miR-216 in stool have the potential of becoming biomarkers for screening PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25485236,"Year":2014,"Title":"MicroRNA expression profiling of diagnostic needle aspirates from surgical pancreatic cancer specimens.","Abstract":"PURPOSE: MicroRNAs (miRNAs) have been widely investigated as potential biomarkers for several malignancies. To establish the feasibility of miRNA expression profiling of small biopsy samples of pancreatic cancers, we assessed expression profiles in freshly collected aspirates obtained immediately after surgical resection of the pancreas. METHODS: We used separate fine needles (20-23 gauge) to aspirate the pancreatic cancer and adjacent normal pancreatic tissue. miRNAs that were differentially expressed in pancreatic cancers and matched paraneoplastic normal pancreatic tissues were identified using an miRNA microarray. RESULTS: We identified 158 aberrantly expressed miRNAs in pancreatic cancers; 51 were overexpressed and 107 underexpressed compared with normal pancreatic tissue. To confirm the microarray findings, quantitative RT-PCR was performed on individual samples. We chose eight miRNAs for further analysis; of which five were overexpressed (miR-21, miR-27a, miR-146a, miR-200a, and miR-196a) and three underexpressed (miR-217, miR-20a, and miR-96) in pancreatic cancer samples compared to benign pancreatic tissue. Expression of miR-21, miR-27a, miR-146a, miR-200a, and miR-196a was significantly increased in cancer fine-needle aspirates relative to matched controls in all samples. Expression of miR-217, miR-20a, and miR-96 was significantly downregulated in almost all pancreatic cancer tissues. CONCLUSION: We demonstrate the feasibility of performing miRNA profiling on very small specimens obtained using fine-needle aspiration of pancreatic cancers.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25384963,"Year":2015,"Title":"Circulating miR-483-3p and miR-21 is highly expressed in plasma of pancreatic cancer.","Abstract":"Several recent studies have revealed that microRNAs (miRNAs) have a role in carcinogenesis and cancer development, and that it is stably detectable in plasma/serum. The aim of this study was to test whether miR483-3p as well as miR21 could be plasma biomarkers for PDAC. The plasma samples were obtained from three groups including 32 pancreatic ductal adenocarcinoma (PDAC) patients, 12 patients with intraductal papillary mucinous neoplasm (IPMN) patients and 30 healthy controls (HC). We evaluated the plasma miR483-3p and miR21 expression level by quantitative RT-PCR. We compared the differences in the plasma level of these miRNAs among the three groups, and investigated the relevance of their plasma expression level to the clinical factors in PDAC. The expressions of miR483-3p and miR21 were detected in all examined plasma samples. The plasma expression levels of these miRNAs were significantly higher in PDAC compared to HC (P<0.01). The plasma miR483-3p expression was significantly higher in PDAC patients than IPMN patients (P<0.05). The plasma miR21 level was associated with advanced stage (P<0.05), metastasis to lymph node and liver (P<0.01), and shorter survival (P<0.01) of the PDAC patients. Together, these findings suggest that measurement of the plasma miR483-3p level is useful for discriminating PDAC from IPMN, and that the plasma miR21 level predicts outcome of PDAC patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25379951,"Year":2014,"Title":"Highly specific plasmonic biosensors for ultrasensitive microRNA detection in plasma from pancreatic cancer patients.","Abstract":"MicroRNAs (miRs) are small noncoding RNAs that regulate mRNA stability and/or translation. Because of their release into the circulation and their remarkable stability, miR levels in plasma and other biological fluids can serve as diagnostic and prognostic disease biomarkers. However, quantifying miRs in the circulation is challenging due to issues with sensitivity and specificity. This Letter describes for the first time the design and characterization of a regenerative, solid-state localized surface plasmon resonance (LSPR) sensor based on highly sensitive nanostructures (gold nanoprisms) that obviates the need for labels or amplification of the miRs. Our direct hybridization approach has enabled the detection of subfemtomolar concentration of miR-X (X = 21 and 10b) in human plasma in pancreatic cancer patients. Our LSPR-based measurements showed that the miR levels measured directly in patient plasma were at least 2-fold higher than following RNA extraction and quantification by reverse transcriptase-polymerase chain reaction. Through LSPR-based measurements we have shown nearly 4-fold higher concentrations of miR-10b than miR-21 in plasma of pancreatic cancer patients. We propose that our highly sensitive and selective detection approach for assaying miRs in plasma can be applied to many cancer types and disease states and should allow a rational approach for testing the utility of miRs as markers for early disease diagnosis and prognosis, which could allow for the design of effective individualized therapeutic approaches.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25350767,"Year":2014,"Title":"A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile.","Abstract":"OBJECTIVES: Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls. METHODS: We identified patients (n=215) with treatment-naive PDAC (n=77), CP with bile/pancreatic duct pathology (n=67), and controls (n=71) who had been prospectively enrolled in a Pancreatobiliary Biorepository at the time of endoscopic retrograde cholangiopancreatography or endoscopic ultrasound. Controls were patients with choledocholithiasis but normal pancreata. The sample was separated into training (n=95) and validation (n=120) cohorts to establish and then test the performance of PDAC Signature Panels in diagnosing PDAC. The training cohort (n=95) included age-matched patients with PDAC, CP, and controls. Panels were derived from the differential expression of 10 candidate miRNAs in plasma or bile. We selected miRNAs having excellent accuracy for inclusion in regression models. RESULTS: Using the training cohort, we confirmed the differential expression of 9/10 miRNAs in plasma (miR-10b, -30c, -106b, -132, -155, -181a, -181b, -196a, and -212) and 7/10 in bile (excluding miR-21, -132, and -181b). Of these, five (miR-10b, -155, -106b, -30c, and -212) had excellent accuracy for distinguishing PDAC. In the training and validation cohorts, the sensitivity/specificity for a PDAC Panel derived from plasma was 95/100% and 100/100%, respectively; in bile, these were 96/100% and 100/100%. CONCLUSIONS: Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC. Additional studies are needed to confirm this Panel and explore its value as a prognostic test.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25216674,"Year":2014,"Title":"MicroRNA-21 inhibits p57Kip2 expression in prostate cancer.","Abstract":"BACKGROUND: p57(Kip2), a cyclin-dependent kinase inhibitor, is considered to be a candidate tumor suppressor gene that has been implicated in Beckwith-Wiedemann syndrome and sporadic cancers. In addition, decreased expression of p57(Kip2) protein has been frequently observed in pancreatic, lung, breast, bladder, gastrointestinal tract and prostate cancers. However, p57(Kip2) gene mutations are rare in these cancers suggesting that other unknown mechanisms might be at play in reducing its expression. The aim of this study was to investigate the molecular mechanism of down-regulation of p57(Kip2) in prostate cancer. FINDINGS: We observed a significant negative correlation between the expression of p57(Kip2) and microRNA-21 (miR-21) in prostate cancer samples and after androgen deprivation with castration in the CWR22 human prostate cancer xenograft model. We report that miR-21 targeted the coding region and decreased p57(Kip2) mRNA and protein levels in prostate cancer cells. Conversely, inhibition of endogenous miR-21 by an anti-miR-21 inhibitor strongly induced p57(Kip2) expression. Furthermore, we found that knockdown of p57(Kip2) reversed the effects of the anti-miR-21 inhibitor on cell migration and anchorage-independent cell growth. CONCLUSIONS: Our results indicate that miR-21 is able to downregulate p57(Kip2) expression by targeting the coding region of the gene and is also able to attenuate p57(Kip2) mediated functional responses. This is the first report demonstrating that p57(Kip2) is a novel target of miR-21 in prostate cancer and revealing a novel oncogenic function of this microRNA.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25184537,"Year":2014,"Title":"A miRNA signature of chemoresistant mesenchymal phenotype identifies novel molecular targets associated with advanced pancreatic cancer.","Abstract":"In this study a microRNA (miRNA) signature was identified in a gemcitabine resistant pancreatic ductal adenocarcinoma (PDAC) cell line model (BxPC3-GZR) and this signature was further examined in advanced PDAC tumor specimens from The Cancer Genome Atlas (TCGA) database. BxPC3-GZR showed a mesenchymal phenotype, expressed high levels of CD44 and showed a highly significant deregulation of 17 miRNAs. Based on relevance to cancer, a seven-miRNA signature (miR-100, miR-125b, miR-155, miR-21, miR-205, miR-27b and miR-455-3p) was selected for further studies. A strong correlation was observed for six of the seven miRNAs in 43 advanced tumor specimens compared to normal pancreas tissue. To assess the functional relevance we initially focused on miRNA-125b, which is over-expressed in both the BxPC3-GZR model and advanced PDAC tumor specimens. Knockdown of miRNA-125b in BxPC3-GZR and Panc-1 cells caused a partial reversal of the mesenchymal phenotype and enhanced response to gemcitabine. Moreover, RNA-seq data from each of 40 advanced PDAC tumor specimens from the TCGA data base indicate a negative correlation between expression of miRNA-125b and five of six potential target genes (BAP1, BBC3, NEU1, BCL2, STARD13). Thus far, two of these target genes, BBC3 and NEU1, that are tumor suppressor genes but not yet studied in PDAC, appear to be functional targets of miR-125b since knockdown of miR125b caused their up regulation. These miRNAs and their molecular targets may serve as targets to enhance sensitivity to chemotherapy and reduce metastatic spread.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25149066,"Year":2014,"Title":"miR-21-3p is a positive regulator of L1CAM in several human carcinomas.","Abstract":"Expression of L1 cell adhesion molecule (L1CAM) occurs frequently in human cancers and is associated with poor prognosis in cancers such as ovarian, endometrial, breast, renal cell carcinoma and pancreatic ductal adenocarcinoma. L1CAM promotes cell motility, invasion, chemoresistance and metastasis formation. Elucidating genetic processes involved in the expression of L1CAM in cancers is of considerable importance. Transcription factors such as SLUG, beta-catenin/TCF-LEF, PAX8 and VHL have been implicated in the re-activation of L1CAM in various types of cancers. There is increasing evidence that micro-RNAs can also have strong effects on gene expression. Here we have identified miR-21-3p as a positive regulator of L1CAM expression. Over-expression of miR-21-3p (miR-21*) but not the complementary sequence miR-21-5p (miR-21) could strongly augment L1CAM expression in renal, endometrial and ovarian carcinoma derived cell lines by an unknown mechanism involving transcriptional activation of the L1CAM gene. In patient cohorts from renal, endometrial and ovarian cancers we observed a strong positive correlation of L1CAM and miR-21-3p expressions. Although L1CAM alone was a reliable marker for overall and disease free survival, the combination of L1CAM and miR-21-3p expressions strongly enhanced the predictive power. Our findings shed new light on the complex regulation of L1CAM in cancers and advocate the use of L1CAM/miR-21-3p for diagnostic application.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25132574,"Year":2014,"Title":"Stromal microRNA-21 levels predict response to 5-fluorouracil in patients with pancreatic cancer.","Abstract":"BACKGROUND AND OBJECTIVES: MicroRNA-21 (miR-21) is upregulated and inversely associated with survival in many cancer types, including pancreatic ductal adenocarcinoma (PDAC). We studied the predictive value of miR-21 levels for gemcitabine or 5-fluorouracil (5-FU) response in tumor cells (TCs) or cancer associated fibroblasts (CAFs) in a cohort of PDAC patients from the RTOG 9704 trial. METHODS: MiR-21 expression in CAFs and TCs, determined by in situ hybridization, of the 229 PDAC subset from RTOG 9704 was correlated with (i) histopathology characteristics using a chi-square test; and (ii) patient overall survival (OS) using the Cox proportional hazards model. RESULTS: MiR-21 was strongly expressed in TCs and CAFs in 137/182 (75%) and 152/181 (84%) PDACs, respectively. MiR-21 expression in CAFs for the group given 5-FU for OS: (i) approached significance in a univariate analysis (hazard ratio [HR], 1.57; 95% confidence interval [CI], 0.95-2.57; P = 0.07); and (ii) was significant in the multivariate model (HR, 1.70; 95% CI, 1.03-2.82; P = 0.038). CONCLUSIONS: MiR-21 expression in CAFs was associated with decreased OS in PDAC patients who received 5-FU, but not gemcitabine. These findings begin to identify stromal miR-21 as a marker to guide chemotherapy choice in PDAC patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25126577,"Year":2014,"Title":"MicroRNA expression in salivary supernatant of patients with pancreatic cancer and its relationship with ZHENG.","Abstract":"In traditional Chinese medicine (TCM), diagnosis and prescriptions are based on the signs and symptoms which are recognized as ZHENG. The cornerstone of TCM is to differentially treat one ZHENG from others, which is also known as syndrome differentiation, and this relies on the gathering of clinical information through inspection, auscultation and olfaction, inquiry, and palpation. However, the biomolecular basis of the ZHENG remains unclear. In this study, the expressions of 384 cancer-related miRNAs in salivary supernatant of patients with pancreatic cancer were assessed by miRNA polymerase chain reaction (PCR) array, and the different expression patterns of miRNA in three different groups of ZHENG were studied with use of real-time quantitative PCR (qRT-PCR). Some miRNAs were found to be specifically expressed in some ZHENGs, for instance, miR-17, miR-21, and miR-181b in Shi-Re ZHENG and miR-196a in Pi-Xu ZHENG. This indicates that these miRNAs may play important roles in different ZHENG condition. Therefore, this study to some extent revealed the molecular basis of TCM ZHENG in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25061297,"Year":2014,"Title":"MicroRNA modulation combined with sunitinib as a novel therapeutic strategy for pancreatic cancer.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and mortal cancer, characterized by a set of known mutations, invasive features, and aberrant microRNA expression that have been associated with hallmark malignant properties of PDAC. The lack of effective PDAC treatment options prompted us to investigate whether microRNAs would constitute promising therapeutic targets toward the generation of a gene therapy approach with clinical significance for this disease. In this work, we show that the developed human serum albumin-1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine:cholesterol/anti-mi croRNA oligonucleotides (+/-) (4/1) nanosystem exhibits the ability to efficiently deliver anti-microRNA oligonucleotides targeting the overexpressed microRNAs miR-21, miR-221, miR-222, and miR-10 in PDCA cells, promoting an almost complete abolishment of microRNA expression. Silencing of these microRNAs resulted in a significant increase in the levels of their targets. Moreover, the combination of microRNA silencing, namely miR-21, with low amounts of the chemotherapeutic drug sunitinib resulted in a strong and synergistic antitumor effect, showing that this combined strategy could be of great importance for therapeutic application in PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":25030590,"Year":2014,"Title":"[Expression and clinical significance of plasma small RNA in patients with pancreatic cancer].","Abstract":"OBJECTIVE: The aim of this study was to identify six miRNAs expressed in plasma of patients with pancreatic cancer (PCa) and analyze their value as a diagnostic index of pancreatic cancer. METHODS: Plasma total RNAs were extracted from 30 PCa patients and 26 normal controls, and the abundance of six microRNAs was measured using real-time PCR. The possibility to combine them with CA19-9 as diagnostic biomarkers was analyzed. RESULTS: The expression level of miR-21, miR-210, miR-155, miR-20a, miR-25 and miR-196a in plasma of patients with pancreatic cancer were 1.65x10(6), 5.98x10(4), 2.83x10(3), 3.47x10(6), 2.76x10(6), and 1.03x10(3) (copies/microl), while the normal controls were 4.08x10(5), 2.54x10(4), 8.55x10(2), 1.79x10(6), 9.32x10(5), and 4.67x10(2) (copies/microl), respectively, with a significant difference between the two groups (P < 0.05). The areas under the ROC curve of miR-21, miR-210, miR-155, miR-20a, miR-25 and miR-196a were 0.893, 0.810, 0.820, 0.766, 0.816 and 0.729, respectively. MiR-21 had the highest diagnostic value when it was used as diagnostic marker alone. The combination of miR-155 and miR-25 was more effective to distinguish PCa from normal than to be used alone, and the area under the ROC curve was 0.913 (95%CI 0.838-0.988) .When CA199 associated with miR -210 and miR-25, respectively, the areas under the ROC curves were 0.96 (95%CI was 0-1.0) and 0.942 (95% CI was 0.876-1.0), which were higher than CA199 alone (0.862, 95%CI was 0.748-0.975). There was a high improvement in diagnostic sensitivity and accuracy when miR-210 and miR-25 were combined with CA19-9, respectively. CONCLUSIONS: Plasma miR-21, miR-155, miR-25, miR-210 have diagnostic value for pancreatic cancer, and deserve further study.","Language":"chi","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":24956938,"Year":2014,"Title":"MicroRNA-196a and -196b as Potential Biomarkers for the Early Detection of Familial Pancreatic Cancer.","Abstract":"Screening programs are recommended for individuals at risk (IAR) from families with familial pancreatic cancer (FPC). However, reliable imaging methods or biomarkers for early diagnosis of pancreatic ductal adenocarcinoma (PC) or its precursor lesions are still lacking. The ability of circulating microRNAs (miRNAs) to discriminate multifocal high-grade precursor lesions or PC from normal was examined. The presence of miRNA-21, -155, -196a, -196b and -210 was analyzed in the serum of transgenic KPC mice to test their ability to distinguish mice with different grades of pancreatic intraepithelial neoplasia (mPanIN1-3) or PC from control mice. Serum levels of miR-196a and -196b were significantly higher in mice with PanIN2/3 lesions (n = 10) or PC (n = 8) as compared to control mice (n = 10) or mice with PanIN1 lesions (n = 10; P = .01). In humans, miR-196a and -196b were also diagnostic. Patients with PC, sporadic (n = 9) or hereditary (n = 10), and IAR with multifocal PanIN2/3 lesions (n = 5) had significantly higher serum levels than patients with neuroendocrine pancreatic tumors (n = 10) or chronic pancreatitis (n = 10), IAR with PanIN1 or no PanIN lesions (n = 5), and healthy controls (n = 10). The combination of both miR-196a and -196b reached a sensitivity of 1 and specificity of 0.9 (area under the curve = 0.99) to diagnose PC or high-grade PanIN lesions. In addition, preoperative elevated serum levels of miR-196a and -196b in patients with PC or multifocal PanIN2/3 lesions dropped to normal after potential curative resection. The combination of miR-196a and -196b may be a promising biomarker test for the screening of IAR for FPC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":24575833,"Year":2014,"Title":"A microRNA meta-signature for pancreatic ductal adenocarcinoma.","Abstract":"Due to its aggressive and late presentation, there is an urgent need for novel and reliable biomarkers for the diagnosis and prognostication of pancreatic ductal adenocarcinoma (PDAC). MiRNAs have been extensively profiled in PDAC tissues, biopsies, blood samples and other biofluids and their expression levels compared to normal and chronic pancreatitis (CP) specimens in order to identify the most relevant candidates. Consolidation of these activities has not been attempted until now. The evaluated meta-review by Ma et al. helps to define the use of miRNAs as biomarkers for detecting this tumor-type and predicting survival outcomes in PDAC. Based on frequency and consistency between microarray studies, they identified a miRNA meta-signature for recognising PDAC: upregulation of miR-21, 23a, 31, 100, 143, 155, and 221; with downregulation of miR-148a, 217 and 375. Furthermore, they validated high miR-21, high miR-31 and low miR-375 tumoural expression as independently prognostic for poor overall-survival (OS; n = 70).","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":24460329,"Year":2013,"Title":"MiR-21 upregulation induced by promoter zone histone acetylation is associated with chemoresistance to gemcitabine and enhanced malignancy of pancreatic cancer cells.","Abstract":"BACKGROUND AND AIMS: MicroRNA-21 (miR-21) is reported to be overexpressed and to contribute to proliferation, apoptosis and gemcitabine resistance in pancreatic ductal adenocarcinomas (PDACs). The aims of this study were to explore regulation of miR-21 expression by epigenetic change and its impact on chemoresistance and malignant properties of of pancreatic cancer. MATERIALS AND METHODS: We retrospectively collected 41 cases of advanced pancreatic cancer patients who were sensitive or resistant to gemcitabine and assessed levels of serum circulating miR-21 for correlation with cytotoxic activity. Histone acetylation in the miR-21 promoter was also studied in gemcitabine-sensitive and gemcitabine-resistant PDAC cells. Gemcitabine-resistant HPAC and PANC-1 cells were transfected with pre-miR-21 precursors (pre-miR-21) and antisense oligonucleotides (anti-miR-21), and were treated with TSA. Finally, invasion and metastasis assays were performed and alteration in mir-21, PTEN, AKT and pAKT level was evaluated in these cells. RESULTS: Serum miR-21 levels were increased in gemcitabine- resistant PDAC patients compared with gemcitabine-sensitive subjects. The miR-21 levels were increased in 6 PDAC cells treated with gemcitabine significantly, associated with 50% inhibitory concentrations (IC50s). Histone acetylation levels at miR-21 promoter were increased in PDAC cells after treatment with gemcitabine. Enhanced invasion and metastasis, increased miR-21 expression, decreased PTEN, elevated pAKT level were demonstrated in gemcitabine-resistant HPAC and PANC-1 cells. Pre-miR-21 transfection or TSA treatment further increased invasion and metastasis ability, decreased PTEN, and elevated pAKT levels in these two lines. In contrast, anti-miR-21 transfection could reverse invasion and metastasis, and PTEN and pAKT expressions induced by gemcitabine. CONCLUSIONS: MiR-21 upregulation induced by histone acetylation in the promoter zone is associated with chemoresistance to gemcitabine and enhanced malignant potential in pancreatic cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":24420840,"Year":2015,"Title":"Prenatal and neonatal exposure to perfluorooctane sulfonic acid results in aberrant changes in miRNA expression profile and levels in developing rat livers.","Abstract":"Perfluorooctane sulfonate (PFOS) is an animal carcinogen. However, the underlying mechanism in cancer initiation is still largely unknown. Recently identified microRNAs (miRNAs) may play an important role in toxicant exposure and in the process of toxicant-induced tumorigenesis. We used PFOS to investigate PFOS-induced changes in miRNA expression in developing rat liver and the potential mechanism of PFOS-induced toxic action. Dams received 3.2 mg/kg PFOS in their feed from gestational day 1 (GD1) to postnatal day 7 (PND 7). Pups then had free access to treated feed until PND 7. We isolated RNAs from liver tissues on PND 1 and 7 and analyzed the expression profiles of 387 known rat miRNAs using microarray technology. PFOS exposure induced significant changes in miRNA expression profiles. Forty-six miRNAs had significant expression alterations on PND 1, nine miRNAs on PND 7. Specifically, expression of four miRNAs was up-regulated on PND 7 but down-regulated on PND1 (p < 0.05). Many aberrantly expressed miRNAs were related to various cancers. We found oncogenic and tumor-suppressing miRNAs, which included miR-19b, miR-21*, miR-17-3p, miR-125a-3p, miR-16, miR-26a, miR-1, miR-200c, and miR-451. In addition, four miRNAs were simultaneous significantly expressed on both PND 1 and 7. Functional Annotation analysis of the predicted transcript targets revealed that PFOS exposure potentially alters pathways associated with different cancers (cancer, melanoma, pancreatic cancer, colorectal cancer, and glioma), biological processes which include positive regulation of apoptosis and cell proliferation. Results showed PFOS exposure altered the expression of a suite of miRNAs. (c) 2014 Wiley Periodicals, Inc. Environ Toxicol 30: 712-723, 2015.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":24120476,"Year":2014,"Title":"MicroRNAs cooperatively inhibit a network of tumor suppressor genes to promote pancreatic tumor growth and progression.","Abstract":"BACKGROUND & AIMS: There has not been a broad analysis of the combined effects of altered activities of microRNAs (miRNAs) in pancreatic ductal adenocarcinoma (PDAC) cells, and it is unclear how these might affect tumor progression or patient outcomes. METHODS: We combined data from miRNA and messenger RNA (mRNA) expression profiles and bioinformatic analyses to identify an miRNA-mRNA regulatory network in PDAC cell lines (PANC-1 and MIA PaCa-2) and in PDAC samples from patients. We used this information to identify miRNAs that contribute most to tumorigenesis. RESULTS: We identified 3 miRNAs (MIR21, MIR23A, and MIR27A) that acted as cooperative repressors of a network of tumor suppressor genes that included PDCD4, BTG2, and NEDD4L. Inhibition of MIR21, MIR23A, and MIR27A had synergistic effects in reducing proliferation of PDAC cells in culture and growth of xenograft tumors in mice. The level of inhibition was greater than that of inhibition of MIR21 alone. In 91 PDAC samples from patients, high levels of a combination of MIR21, MIR23A, and MIR27A were associated with shorter survival times after surgical resection. CONCLUSIONS: In an integrated data analysis, we identified functional miRNA-mRNA interactions that contribute to growth of PDACs. These findings indicate that miRNAs act together to promote tumor progression; therapeutic strategies might require inhibition of several miRNAs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":24007214,"Year":2013,"Title":"Analysis of serum exosomal microRNAs and clinicopathologic features of patients with pancreatic adenocarcinoma.","Abstract":"BACKGROUND: Altered expression of serum microRNAs (miRNAs) have been reported to correlate with carcinogenesis and progression of pancreatic adenocarcinoma (PC), but descriptions of serum exosomal miRNAs in PC are still lacking. This study was designed to evaluate serum exosomal miRNA levels in PC patients and to investigate their relationships with clinicopathologic features and prognosis. METHODS: Four miRNAs (miR-17-5p, miR-21, miR-155 and miR-196a) related to PC were selected for examination in our research. Serum miRNA was examined by RT-PCR in a group of 49 patients, including 22 with PCs, 6 with benign pancreatic tumors, 7 with ampullary carcinomas, 6 with chronic pancreatitis and 8 healthy participants. The clinicopathologic data were also collected, and PC patients were classified according to the presence of metastasis, tumor differentiation and advanced stage. RESULTS: There were low expressions of exosomal miR-155 and miR-196a in serum samples of PC patients when U-6 was used as a control. Serum exosomal miR-17-5p was higher in PC patients than in non-PC patients and healthy participants. High levels of miR-17-5p were significantly correlated with metastasis and advanced stage of PC. The serum exosomal miR-21 level in PC was higher than that in the normal and chronic pancreatitis groups, but was not significantly correlated with PC differentiation and tumor stage. CONCLUSIONS: There were high expressions of serum exosomal miR-17-5p and miR-21 in PC patients. Examination of serum exosomal microRNA is a useful serum biomarker for PC diagnosis other than serum-free microRNA. It is postulated that exosomal miR-17-5p participates in the progression of PC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23991015,"Year":2013,"Title":"MicroRNA-21 in pancreatic ductal adenocarcinoma tumor-associated fibroblasts promotes metastasis.","Abstract":"INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is projected to rise to the second leading cause of U.S. cancer-related deaths by 2020. Novel therapeutic targets are desperately needed. MicroRNAs (miRs) are small noncoding RNAs that function by suppressing gene expression and are dysregulated in cancer. miR-21 is overexpressed in PDAC tumor cells (TC) and is associated with decreased survival, chemoresistance and invasion. Dysregulation of miR regulatory networks in PDAC tumor-associated fibroblasts (TAFs) have not been previously described. In this study, we show that miR-21 expression in TAFs promotes TC invasion. METHODS: In-situ hybridization for miR-21 was performed on the 153 PDAC patient UCLA tissue microarray and 23 patient-matched lymph node metastases. Stromal and TC histoscores were correlated with clinicopathologic parameters by univariate and multivariate Cox regression. miR-21 positive cells were further characterized by immunofluorescence for mesenchymal/epithelial markers. For in vitro studies, TAFs were isolated from freshly resected human PDAC tumors by the outgrowth method. miR-21 was overexpressed/inhibited in fibroblasts and then co-cultured with GFP-MiaPaCa TCs to assess TC invasion in modified Boyden chambers. RESULTS: miR-21 was upregulated in TAFs of 78% of tumors, and high miR-21 significantly correlated with decreased overall survival (P = 0.04). Stromal miR-21 expression was also significantly associated with lymph node invasion (P = 0.004), suggesting that it is driving TC spread. Co-immunofluorescence revealed that miR-21 colocalized with peritumoral fibroblasts expressing alpha-smooth muscle actin. Moreover, expression of miR-21 in primary TAFs correlated with miR-21 in TAFs from patient-matched LN metastases; evidence that PDAC tumor cells induce TAFs to express miR-21. miR-21 expression in TAFs and TCs promotes invasion of TCs and is inhibited with anti-miR-21. CONCLUSIONS: miR-21 expression in PDAC TAFs is associated with decreased overall survival and promotes TC invasion. Anti-miR-21 may represent a novel therapeutic strategy for dual targeting of both tumor and stroma in PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23933230,"Year":2013,"Title":"MicroRNAs as diagnostic markers for pancreatic ductal adenocarcinoma and its precursor, pancreatic intraepithelial neoplasm.","Abstract":"Since the discovery of small non-coding RNAs, the analysis of microRNA (miRNA) expression patterns in human cancer have provided new insights into cancer biology. Evidence suggests that deregulated miRNA expression is associated with pancreatic cancer development. In this study, we analyzed the expression of several miRNAs in different types of pancreatic disease to determine if miRNA expression could aid in the diagnosis of pancreatic ductal adenocarcinoma (PDAC) and its precursor, pancreatic intraepithelial neoplasm (PanIN). Pancreatic resection specimens were selected, which included PDAC (n = 16), benign pancreatic parenchyma from corresponding carcinoma cases (n = 16), chronic pancreatitis (n = 4), normal pancreatic parenchyma (n = 5), and PanIN (n = 5). The expression levels of five miRNA (miR-148a, miR-217, miR-21, miR-196a, and miR-10b) were assessed by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays. Our data demonstrate that compared to the normal pancreatic parenchyma, miR-148a and miR-217 expression levels were down-regulated in PanIN, particularly in PanIN II-III and PDAC, whereas the level of miR-196 was significantly up-regulated in PDAC and its precursor, PanIN II-III. In addition, we observed that miR-21 was significantly overexpressed in PDAC, and miR-10b was highly expressed in PanIN II-III. Our study demonstrates that certain miRNAs, especially miR-148a, miR-217, and miR-196a, are significantly deregulated in PDAC, including in the early stage of PDAC. These markers can potentially be used as diagnostic markers to distinguish PDAC and its precursor from benign lesions.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23776656,"Year":2013,"Title":"Real-time monitoring of miRNA function in pancreatic cell lines using recombinant AAV-based miRNA Asensors.","Abstract":"BACKGROUND: MicroRNAs (miRNAs) are reportedly involved in pancreatic ductal adenocarcinoma (PDAC) development. Current methods do not allow us to reliably monitor miRNA function. Asensors are adeno-associated virus (AAV) vector miRNA sensors for real-time consecutive functional monitoring of miRNA profiling in living cells. METHODS: miR-200a, -200b, -21, -96, -146a, -10a, -155, and -221 in three PDAC cell lines (BxPC-3, CFPAC-1, SW1990), pancreatic epithelioid carcinoma cells (PANC-1), and human pancreatic nestin-expressing cells (hTERT-HPNE) were monitored by Asensors. Subsequently, the real-time consecutive functional profile of all miRNAs was evaluated. RESULTS: Selected miRNAs were detectable in all cell lines with high sensitivity and reproducibility. In the three PDAC cell lines, BxPC-3, CFPAC-1, and SW1990, the calibrated signal unit of the eight miRNAs Asensors was significantly lower than that of the Asensor control. However, in PANC-1 cells, miR-200a and -155 showed upregulation of target gene expression at 24 hours after infection with the sensors; at 48 hours, miR-200b and -155 displayed upregulation of reporter expression; and at 72 hours, reporter gene expression was upregulated by miR-200a and -200b. The result that miRNA could upregulate gene expression was further confirmed in miR-155 of hTERT-HPNE cells. Furthermore, miRNA activity varied among cell/tissue types and time. CONCLUSION: It is possible that miRNA participates in the pathophysiology of pancreatic cancer, but the current popular methods do not accurately reveal the real-time miRNA function. Thus, this report provided a convenient, accurate, and sensitive approach to miRNA research.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23752880,"Year":2013,"Title":"Endoscopically acquired pancreatic cyst fluid microRNA 21 and 221 are associated with invasive cancer.","Abstract":"OBJECTIVES: Pancreatic cysts are a group of lesions with heterogeneous malignant potential. Currently, there are no reliable biomarkers to aid in cyst diagnosis and classification. The objective of this study was to identify potential microRNA (miR) biomarkers in endoscopically acquired pancreatic cyst fluid that could be used to distinguish between benign, premalignant, and malignant cysts. METHODS: A list of candidate miRs was developed using a whole-genome expression array analysis of pancreatic cancer (pancreatic ductal adenocarcinoma) and nonmalignant samples overlapped with existing literature and predicted gene targets. Endoscopically acquired pancreatic cyst fluid samples were obtained from a group of 38 patients who underwent cyst fluid aspiration and surgical resection. Selected miR expression levels in cyst fluid samples were assessed by quantitative real-time-PCR. Additionally, in situ hybridization (ISH) on corresponding cyst tissue samples was performed to identify the source and validate the expression level of fluid miRs. RESULTS: Of the six miRs that were profiled in the study, two showed differential expression in malignant cysts. miR-221 was expressed at significantly higher levels in malignant cysts compared with benign or premalignant cysts (P=0.05). miR-21 was also expressed at significantly higher levels in malignant cysts (P<0.01). Additionally, the expression of miR-21 was significantly higher in premalignant cysts than benign cysts (P=0.03). The differential expression of miR-21 among cyst categories was confirmed by ISH. CONCLUSIONS: In this small single-center study, miRs are potential pancreatic cyst fluid diagnostic biomarkers. In particular, miR-21 is identified as a candidate biomarker to distinguish between benign, premalignant, and malignant cysts. Additionally miR-221 may be of use in the identification of more advanced malignant disease.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23726431,"Year":2013,"Title":"Hypoxia induces the overexpression of microRNA-21 in pancreatic cancer cells.","Abstract":"BACKGROUND: Pancreatic cancer cells exist in a hypoxic microenvironment containing numerous factors that impact tumor survival, proliferation, and metastasis. MicroRNAs (miRs) are differentially expressed in cancer but also altered by hypoxia. We hypothesized that hypoxia could induce expression of miR-21, an oncomir in pancreatic cancer cells. MATERIALS AND METHODS: We examined how hypoxia regulates miR-21 expression in pancreatic cancer cell lines (BxPC-3, AsPC-1) by stem-loop RT-PCR. Chromatin immunoprecipitation assays were used to study how hypoxia alters hypoxia-inducible factor (HIF)-1alpha binding to the hypoxia response element of miR-21. BxPC-3 and AsPC-1 cells were transfected with a constitutively stable HIF-1alpha subunit or vector control (pcDNA3.1) to determine the influence of miR-21 in normoxia. The effect of mature miR-21 sense and antisense oligonucleotides on proliferation and apoptosis in hypoxic and normoxic conditions was assessed via WST-1 assay and flow cytometry. RESULTS: MiR-21 levels increased in all cell lines grown in hypoxic conditions versus normoxia, whereas siRNA targeting HIF-1alpha reduced miR-21 expression. Hypoxic conditions resulted in direct binding of HIF-1alpha to the predicted binding site in miR-21. Transfection with a constitutively stable HIF-1alpha expression plasmid in normoxia resulted in upregulated miR-21, similar to that seen in hypoxia. Cells transfected with antisense constructs targeting miR-21 had reduced proliferation and increased apoptosis in normoxia, whereas miR-21 overexpression abrogated hypoxia-associated reductions in proliferation. CONCLUSIONS: MiR-21 is induced by hypoxia in pancreatic cancer cells via HIF-1alpha upregulation. MiR-21 overexpression allows cells to avoid apoptosis in a hypoxic microenvironment. Inhibition of miR-21 expression may increase cellular susceptibility to hypoxia in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23638815,"Year":2013,"Title":"Distinct miRNA profiles are associated with malignant transformation of pancreatic cystic tumors revealing potential biomarkers for clinical use.","Abstract":"Pancreatic cysts are now being detected more frequently owing to increased recognition and the liberal use of cross-sectional imaging. There is a spectrum of pancreatic cystic lesions ranging from the completely benign inflammatory to the highly malignant. Pancreatic cystic tumors, especially those with a mucinous epithelial lining such as the intraductal papillary mucinous neoplasms (IPMNs), have the potential to become malignant. The evaluated paper provides further evidence for miRNAs as diagnostic biomarkers for detecting dysplastic and malignant change in IPMNs, which may be useful for future clinical decision making. IPMNs of varying degrees of dysplasia, as well as IPMN with carcinoma, pancreatic ductal adenocarcinoma and normal pancreas samples were examined by microarray. Upregulation of miR-21, miR-155 and miR-708 was found to occur during IPMN malignant transformation. Here, the authors evaluate the published miRNA profiles of premalignant pancreatic lesions in order to consolidate these data.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23564788,"Year":2013,"Title":"Chemosensitivity induced by down-regulation of microRNA-21 in gemcitabine-resistant pancreatic cancer cells by indole-3-carbinol.","Abstract":"BACKGROUND/AIM: Overexpression of microRNA-21 (miR-21) indicates chemoresistance in pancreatic cancer. We evaluated the change of chemosensitivity to gemcitabine through the down-regulation of miR-21 in human pancreatic cancer cells (Panc-1). MATERIALS AND METHODS: The efficacy of indole-3-carbinol (I3C) in suppressing miR-21 expression and its anticancer effect in combination with gemcitabine were investigated. RESULTS: Down-regulation of miR-21 by I3C was positively-correlated in a time- and dose-dependent manner. I3C and gemcitabine combination therapy increased cytotoxicity in Panc-1 cells. Transfection of miR-21 mimic abrogated I3C-induced sensitivity to gemcitabine. DNA fragmentation and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays showed that pre-treatment with I3C enhanced apoptosis and this effect was attenuated by miR-21 transfection. The expression of programmed cell death-4 (PDCD4) was increased by I3C and reduced by miR-21 transfection. CONCLUSION: I3C would be effective for enhancing sensitivity of pancreatic cancer cells to gemcitabine via down-regulation of miR-21. Such enhanced chemosensitivity might be explained by the increased expression of PDCD4, which is a downstream target which miR-21 negatively regulates.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23481326,"Year":2013,"Title":"Targeting miR-21 for the therapy of pancreatic cancer.","Abstract":"Despite tremendous efforts worldwide from clinicians and cancer scientists, pancreatic ductal adenocarcinoma (PDA) remains a deadly disease for which no cure is available. Recently, microRNAs (miRNAs) have emerged as key actors in carcinogenesis and we demonstrated that microRNA-21 (miR-21), oncomiR is expressed early during PDA. In the present study, we asked whether targeting miR-21 in human PDA-derived cell lines using lentiviral vectors (LVs) may impede tumor growth. We demonstrated that LVs-transduced human PDA efficiently downregulated miR-21 expression, both in vitro and in vivo. Consequently, cell proliferation was strongly inhibited and PDA-derived cell lines died by apoptosis through the mitochondrial pathway. In vivo, miR-21 depletion stopped the progression of a very aggressive model of PDA, to induce cell death by apoptosis; furthermore, combining miR-21 targeting and chemotherapeutic treatment provoked tumor regression. We demonstrate herein for the first time that targeting oncogenic miRNA strongly inhibit pancreatic cancer tumor growth both in vitro and in vivo. Because miR-21 is overexpressed in most human tumors; therapeutic delivery of miR-21 antagonists may still be beneficial for a large number of cancers for which no cure is available.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23359184,"Year":2013,"Title":"Resveratrol induces apoptosis of pancreatic cancers cells by inhibiting miR-21 regulation of BCL-2 expression.","Abstract":"OBJECTIVE: Resveratrol is an edible polyphenolic phytoalexin present in different plant species and plays important role in inhibiting proliferation and inducing apoptosis of pancreatic cancer cells. In this paper, the mechanism of resveratrol on PANC-1, CFPAC-1 and MIA Paca-2 cells apoptosis was examined. METHODS: We first evaluated the effect of resveratrol on viability of PANC-1, CFPAC-1 and MIA Paca-2 cells using MTT assay. Next, we performed real-time PCR to assess the effect of resveratrol on miR-21 expression. We also used Western blot to measure BCL-2 protein levels after down-regulation of miR-21 expression. Finally, we evaluated the effect of miR-21 on resveratrol-induced anti-tumor activity using miR-21 mimic. RESULTS: Resveratrol induced a significant inhibition of PANC-1, CFPAC-1 and MIA Paca-2 cells viability in a dose-dependent manner. Resveratrol also decreased the expression of miR-21. Besides, down-regulation of miR-21 expression can inhibit BCL-2 expression in PANC-1, CFPAC-1 and MIA Paca-2 cells. Over-expression of miR-21 expression can reverse down-regulation of BCL-2 expression and apoptosis induced by resveratrol. CONCLUSIONS: In this study, we demonstrated that the effect of resveratrol on apoptosis is due to inhibiting miR-21 regulation of BCL-2 expression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23293055,"Year":2013,"Title":"Garcinol sensitizes human pancreatic adenocarcinoma cells to gemcitabine in association with microRNA signatures.","Abstract":"BACKGROUND: Alterations in microRNA (miRNA/miR) genes are of biological importance in the pathophysiology of cancers, including pancreatic cancer (PaCa). Although growing evidence supports the role of miRNA in cancer, their response to dietary phytochemicals is less known. Previously, we showed that garcinol induces PaCa cell growth arrest and apoptosis in vitro. The present study, discusses chemo-sensitization by garcinol in synergism with first-line PaCa drug, gemcitabine. The miRNA expression profile of gemcitabine-resistant Panc-1 cells treated with garcinol and/or gemcitabine was also evaluated. METHODS AND RESULTS: Garcinol synergizes with gemcitabine to inhibit cell proliferation and induce apoptosis in PaCa cells with significant modulation of key cancer regulators including PARP, VEGF, MMPs, ILs, caspases, and NF-kappaB. In addition, biostatistical analyses, quantitative reverse transcription PCR data, and in silico modeling using TargetScan5, PicTar, and DNA intelligent analysis, microT-V.B4 database showed that these two agents modulated a number of microRNAs (miR-21, miR-196a, miR-495, miR-605, miR-638, and miR-453) linked to various canonical oncogenic signaling pathways. CONCLUSION: We identified garcinol-specific miRNA biomarkers that sensitize PaCa cells to gemcitabine treatment, thus attenuating the drug-resistance phenotype. These results prompt further interest in garcinol and gemcitabine combination strategy as a drug modality to improve treatment outcome in patients diagnosed with PaCa.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23272057,"Year":2012,"Title":"Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment.","Abstract":"Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF) has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s) by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC) cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1alpha, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23256701,"Year":2013,"Title":"Towards a clinical use of miRNAs in pancreatic cancer biopsies.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, despite advances in imaging, surgery and a greater understanding of its molecular biology. Patient outcomes remain poor due to an inability to detect disease early and resistance to anticancer treatments. miRNAs are promised to become ideal cancer biomarkers, as they are tumor and tissue specific and also incredibly stable molecules. So far, large profiling studies of the PDAC miRNome have identified the 'usual suspects' known to be deregulated in solid tumors, such as oncomiR-21, as well as others that could be more robust for differentiating malignant from benign pancreatic disease. However, many of these are yet to be validated clinically. The paper under evaluation provides further evidence for the use of miRNAs as diagnostic biomarkers for PDAC. We have reviewed the use of miRNAs as diagnostic analytes for detecting PDAC in biopsies.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23177026,"Year":2013,"Title":"The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL.","Abstract":"miR-21 expression in cancer tissue has been reported to be associated with the clinical outcome and activity of gemcitabine in pancreatic cancer. However, resection is possible in only a minority of patients due to the advanced stages often present at the time of diagnosis, and safely obtaining sufficient quantities of pancreatic tumor tissue for molecular analysis is difficult at the unresectable stages. In this study, we investigated whether the serum level of miR-21 could be used as a predictor of chemosensitivity. We tested the levels of serum miR-21 in a cohort of 177 cases of advanced pancreatic cancer who received gemcitabine-based palliative chemotherapy. We found that a high level of miR-21 in the serum was significantly correlated with a shortened time-to-progression (TTP) and a lower overall survival (OS). The serum miR-21 level was an independent prognostic factor for both the TTP and the OS (HR 1.920; 95% CI, 1.274-2.903, p = 0.002 for TTP and HR 1.705; 95% CI, 1.147-2.535, p = 0.008 for OS). The results from a functional study showed that gemcitabine exposure down-regulated miR-21 expression and up-regulated FasL expression. The increased FasL expression following gemcitabine treatment induced cancer cell apoptosis, whereas the ectopic expression of miR-21 partially protected the cancer cells from gemcitabine-induced apoptosis. Additionally, we confirmed that FasL was a direct target of miR-21. Therefore, the serum level of miR-21 may serve as a predictor of chemosensitivity in advanced pancreatic cancer. Additionally, we identified a new mechanism of chemoresistance mediated by the effects of miR-21 on the FasL/Fas pathway.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":23139258,"Year":2013,"Title":"The good, the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms.","Abstract":"BACKGROUND: This multicenter study evaluated three candidate microRNAs (miRNAs) (miR-21, miR-155 and miR-101) as potential biomarkers in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. PATIENTS AND METHODS: miRNA expression was quantified by quantitative RT-PCR in 86 laser-microdissected specimens, including 65 invasive IPMNs, 16 non-invasive IPMNs and 5 normal pancreatic ductal tissues. Univariate and multivariate analyses compared miRNAs and clinical parameters with overall (OS) and disease-free survival (DFS). RESULTS: miR-21 and miR-155 were up-regulated in invasive IPMNs compared with non-invasive IPMNs, as well as in non-invasive IPMNs compared with normal tissues. Conversely, miR-101 levels were significantly higher in non-invasive IPMNs and normal tissues compared with invasive IPMNs. High levels of miR-21 were associated with worse OS [hazard ratio (HR) = 2.47, 95% confidence interval (CI) = 1.37-5.65, P = 0.0047]. Patients with high-miR-21 expression also had a shorter median DFS (10.9 versus 29.9 months, P = 0.01). Multivariate analysis confirmed miR-21 as independently prognostic for mortality and disease progression (death risk: HR = 3.3, 95% CI = 1.5-7.0, P = 0.02; progression risk: HR = 2.3, 95% CI = 1.2-4.8, P = 0.02), as well as positive lymph-node status (death risk: HR = 2.6, 95% CI = 1.1-6.3, P = 0.03; progression risk: HR = 2.2, 95% CI = 1.0-4.8, P = 0.04). CONCLUSIONS: miR-21, miR-155 and miR-101 showed significant differences in invasive versus non-invasive IPMNs. miR-21 emerged as an independent prognostic biomarker in invasive IPMNs and should be validated in prospective studies.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22905187,"Year":2012,"Title":"Feasibility of fecal microRNAs as novel biomarkers for pancreatic cancer.","Abstract":"INTRODUCTION: Pancreatic cancer (PCA) is an aggressive tumor that associates with high mortality rates. Majority of PCA patients are diagnosed usually at late tumor stages when the therapeutic options are limited. MicroRNAs (miRNA) are involved in tumor development and are commonly dysregulated in PCA. As a proof-of-principle study, we aimed to evaluate the potential of fecal miRNAs as biomarkers for pancreatic cancer. MATERIALS AND METHODS: Total RNA was extracted from feces using Qiagen's miRNA Mini Kit. For miRNA expression analyses we selected a subset of 7 miRNAs that are frequently dysregulated in PCA (miR-21, -143, -155, -196a, -210, -216a, -375). Subsequently, expression levels of these miRNAs were determined in fecal samples from controls (n = 15), chronic pancreatitis (n = 15) and PCA patients (n = 15) using quantitative TaqMan-PCR assays. RESULTS: All selected miRNAs were detectable in fecal samples with high reproducibility. Four of seven miRNAs (miR-216a, -196a, -143 und -155) were detected at lower concentrations in feces of PCA patients when compared to controls (p<0.05). Analysis of fecal miRNA expression in controls and patients with chronic pancreatitis and PCA revealed that the expression of miR-216a, -196a, -143 und -155 were highest in controls and lowest in PCA. The expression of the remaining three miRNAs (miR-21, -210 and -375) remained unchanged among controls and the patients with either chronic pancreatitis or PCA. CONCLUSION: Our data provide novel evidence for the differential expression of miRNAs in feces of patients with PCA. If successfully validated in large-scale prospective studies, the fecal miRNA biomarkers may offer novel tools for PCA screening research.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22850622,"Year":2013,"Title":"Expression of microRNAs in patients with pancreatic cancer and its prognostic significance.","Abstract":"OBJECTIVES: Investigation of expression profile of well-established microRNAs in pancreatic adenocarcinoma, and its correlation with clinicopathological factors. METHODS: Eighty-eight samples of ductal pancreatic adenocarcinoma and 98 control samples were analyzed by real-time polymerase chain reaction for miR-21, miR-31, miR-122, miR-145, miR-146a, miR-155, miR-210, and miR-222 expressions. The results were normalized and then statistically analyzed using nonparametric statistical tests. RESULTS: According to our results, miR-21, miR-155, miR-210, miR-221, and miR-222, were overexpressed in diseased tissues than in the control samples, whereas miR-31, miR-122, miR-145, and miR-146a were underexpressed. Additionally, the expressions of miR-21 and miR-155 were associated with tumor stage and poor prognosis. CONCLUSIONS: The tumorigenic role of miR-21 and miR-155 was confirmed, whereas down-regulation of miR-31, miR-145, and miR-146a, in dispute with current literature, renders necessary the revision of use of microRNAs as biological markers.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22836856,"Year":2012,"Title":"Changes in miR-143 and miR-21 expression and clinicopathological correlations in pancreatic cancers.","Abstract":"OBJECTIVES: Despite advances in clinical management of pancreatic cancer (PC), there is still room for improvement in early detection, diagnosis, and treatment strategies. The role of microRNAs (miRNAs) in tumor biology might pinpoint an alteration in expression of miRNAs as new diagnostic/prognostic biomarkers. METHODS: Expression levels of miR-143 and miR-21 and correlations with clinicopathological features were analyzed in 26 matched pairs of tumor and adjacent noncancerous tissue samples collected from patients with PCs, including 18 pancreatic ductal adenocarcinomas (PDACs) and 8 adenocarcinomas of Vater's papilla (PVACs). RESULTS: Compared to normal tissues, miR-143 was up-regulated in both PDAC and PVAC tumor samples (P = 0.0028 and P = 0.039, respectively). Conversely, alterations in miR-21 expression were significantly different in PDAC versus PVAC samples (P = 0.0049). Tumor levels of miR-21 were associated with preoperative serum levels of CA 19-9 (r = 0.63, P = 0.0022), whereas miR-143 expression was negatively correlated to lymph node spreading (r = -0.64; P = 0.0004). Correlation between miR-143 and miR-21 expression levels in patients with PDAC was observed (r = 0.53, P = 0.023). CONCLUSIONS: Deregulation of miR-143 and miR-21 may reflect histological features and biological behavior of different PCs. Association data with clinical parameters might indicate a prognostic significance for miR-143 and miR-21 in PCs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22513294,"Year":2012,"Title":"Circulating microRNAs in serum of human K-ras oncogene transgenic rats with pancreatic ductal adenocarcinomas.","Abstract":"OBJECTIVES: Novel biomarkers for pancreatic ductal adenocarcinoma (PDAC) are urgently needed because of its poor prognosis. We have previously established an animal model for human PDAC using transgenic rats in which expression of a human K-ras(G12V) oncogene is regulated by the Cre/lox system. Using this model, we searched for candidate circulating microRNAs (miRNAs) for use as novel clinical diagnostic biomarkers for PDAC. METHODS: Rats bearing PDACs were generated using our model. MicroRNA expression in serum and pancreatic tissues of PDAC and control rats was compared by microarray analysis. Rat serum levels of 28 miRNAs identified by microarray analysis and 4 miRNAs previously reported to be high in plasma of PDAC patients were quantified by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: Quantification by real-time quantitative polymerase chain reaction revealed that miR-155, miR-21, and miR-210 were higher in serum of PDAC rats, similar to plasma of patients with PDAC. In addition, miR-18a, miR-203, miR-30b-5p, miR-31, miR-369-5p, miR-376a, and miR-541 were higher and miR-375 was lower in the serum of PDAC rats. CONCLUSION: We identified 4 previously unreported miRNAs (miRNA-203, miRNA-369-5p, miRNA-376a, and miRNA-375) whose expression is significantly different in PDAC rats compared to control rats. These miRNAs need to be quantitated in humans as potential novel clinical diagnostic biomarkers for PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22504911,"Year":2012,"Title":"Differential signature of fecal microRNAs in patients with pancreatic cancer.","Abstract":"The potential value of microRNAs as new biomarkers for pancreatic cancer (PCa) screening was explored in this study. Fecal microRNAs from stool samples obtained from 29 PCa patients, 22 chronic pancreatitis (CP) patients and 13 normal individuals were extracted, and 7 microRNAs (miR-16, miR-21, miR-155, miR-181a, miR-181b, miR-196a and miR-210) were detected. miR-181b and miR-210 discriminated PCa from normal individuals with receiver operating characteristic (ROC) curves and area under curve (AUC-ROC) of 0.745 and 0.772, respectively. There was a significant correlation between miR196a and the maximum tumor diameter (Spearman r = 0.516, P = 0.041). These findings suggest that fecal microRNAs such as miR-181b and miR-210 may have potential to be used as new biomarkers for PCa screening.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22466166,"Year":2012,"Title":"MicroRNA expression aids the preoperative diagnosis of pancreatic ductal adenocarcinoma.","Abstract":"OBJECTIVES: This study aimed to evaluate microRNA (miRNA) expression in pancreatic resection specimens and fine needle aspiration biopsies and determine which, if any, miRNAs aid the distinction between benign and malignant pancreatic tumors in limited cytology material. METHODS: Resection specimens containing adenocarcinoma (n = 17), intraductal papillary mucinous neoplasms (n = 11), and nonneoplastic tissues (n = 15) were evaluated for miR-21, miR-221, miR-100, miR-155, and miR-181b expression by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and a subset of carcinomas and intraductal papillary mucinous neoplasms was analyzed with miRNA microarrays. Cellblocks containing carcinoma (n = 26) or benign pancreatic lesions (n = 11) from fine needle aspiration biopsies were subjected to qRT-PCR for miR-21, miR-221, miR-181b, miR-196a, and miR-217. RESULTS: Carcinomas showed higher expression of miR-21, miR-221, miR-155, miR-100, and miR-181b than benign lesions by qRT-PCR, and overexpression of miR-21, miR-221, and miR-181b was confirmed by microarray analysis. Cellblocks containing carcinoma showed higher expression of miR-21, miR-221, and miR-196a than those from benign lesions (P < 0.001, P = 0.009, and P < 0.001, respectively). CONCLUSIONS: Pancreatic ductal adenocarcinomas show differential expression of miRNAs compared to benign pancreatic lesions. A select panel of miRNAs aids the distinction between pancreatic lesions in cytology specimens.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22384141,"Year":2012,"Title":"MicroRNAs targeting oncogenes are down-regulated in pancreatic malignant transformation from benign tumors.","Abstract":"BACKGROUND: MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with pre-malignant pancreatic tumors. We wished to compare the miRNA expression signatures in pancreatic benign cystic tumors (BCT) of low and high malignant potential with PDAC, in order to identify miRNAs deregulated during PDAC development. The mechanistic consequences of miRNA dysregulation were further evaluated. METHODS: Tissue samples were obtained at a tertiary pancreatic unit from individuals with BCT and PDAC. MiRNA profiling was performed using a custom microarray and results were validated using RT-qPCR prior to evaluation of miRNA targets. RESULTS: Widespread miRNA down-regulation was observed in PDAC compared to low malignant potential BCT. We show that amongst those miRNAs down-regulated, miR-16, miR-126 and let-7d regulate known PDAC oncogenes (targeting BCL2, CRK and KRAS respectively). Notably, miR-126 also directly targets the KRAS transcript at a \"seedless\" binding site within its 3'UTR. In clinical specimens, miR-126 was strongly down-regulated in PDAC tissues, with an associated elevation in KRAS and CRK proteins. Furthermore, miR-21, a known oncogenic miRNA in pancreatic and other cancers, was not elevated in PDAC compared to serous microcystic adenoma (SMCA), but in both groups it was up-regulated compared to normal pancreas, implicating early up-regulation during malignant change. CONCLUSIONS: Expression profiling revealed 21 miRNAs down-regulated in PDAC compared to SMCA, the most benign lesion that rarely progresses to invasive carcinoma. It appears that miR-21 up-regulation is an early event in the transformation from normal pancreatic tissue. MiRNA expression has the potential to distinguish PDAC from normal pancreas and BCT. Mechanistically the down-regulation of miR-16, miR-126 and let-7d promotes PDAC transformation by post-transcriptional up-regulation of crucial PDAC oncogenes. We show that miR-126 is able to directly target KRAS; re-expression has the potential as a therapeutic strategy against PDAC and other KRAS-driven cancers.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22213426,"Year":2012,"Title":"Inactivation of Ink4a/Arf leads to deregulated expression of miRNAs in K-Ras transgenic mouse model of pancreatic cancer.","Abstract":"Human pancreatic cancer (PC) is an aggressive disease, which has been recapitulated in transgenic animal model that provides unique opportunity for mechanistic understanding of disease progression and also for testing the efficacy of novel therapeutics. Emerging evidence suggests deregulated expression of microRNAs (miRNAs) in human PC, and thus we investigated the expression of miRNAs in pancreas tissues obtained from transgenic mouse models of K-Ras (K), Pdx1-Cre (C), K-Ras;Pdx1-Cre (KC), and K-Ras;Pdx1-Cre;INK4a/Arf (KCI), initially from pooled RNA samples using miRNA profiling, and further confirmed in individual specimens by quantitative RT-PCR. We found over-expression of miR-21, miR-221, miR-27a, miR-27b, and miR-155, and down-regulation of miR-216a, miR-216b, miR-217, and miR-146a expression in tumors derived from KC and KCI mouse model, which was consistent with data from KCI-derived RInk-1 cells. Mechanistic investigations revealed a significant induction of EGFR, K-Ras, and MT1-MMP protein expression in tissues from both KC and KCI mouse compared to tissues from K or C, and these results were consistent with similar findings in RInk-1 cells compared to human MIAPaCa-2 cells. Furthermore, miR-155 knock-down in RInk-1 cells resulted in the inhibition of cell growth and colony formation consistent with down-regulation of EGFR, MT1-MMP, and K-Ras expression. In addition, miR-216b which target Ras, and forced re-expression of miR-216b in RInk-1 cells showed inhibition of cell proliferation and colony formation, which was correlated with reduced expression of Ras, EGFR, and MT1-MMP. These findings suggest that these models would be useful for preclinical evaluation of novel miRNA-targeted agents for designing personalized therapy for PC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22194634,"Year":2012,"Title":"Serum microRNA expression profile as a biomarker in the diagnosis and prognosis of pancreatic cancer.","Abstract":"BACKGROUND: Detection of pancreatic cancer (PaC), particularly at early stages, remains a great challenge owing to lack of specific biomarkers. We sought to identify a PaC-specific serum microRNA (miRNA) expression profile and test its specificity and sensitivity as a biomarker in the diagnosis and prognosis of PaC. METHODS: We obtained serum samples from 197 PaC cases and 158 age- and sex-matched cancer-free controls. We screened the differentially expressed serum miRNAs with Illumina sequencing by synthesis technology using pooled serum samples followed by RT-qPCR validation of a large number of samples arranged in multiple stages. We used risk score analysis to evaluate the diagnostic value of the serum miRNA profiling system. To assess the serum miRNA-based biomarker accuracy in predicting PaC, we performed additional double-blind testing in 77 PaC cases and 52 controls and diagnostic classification in 55 cases with clinically suspected PaC. RESULTS: After the selection and validation process, 7 miRNAs displayed significantly different expression levels in PaC compared with controls. This 7 miRNA-based biomarker had high sensitivity and specificity for distinguishing various stages of PaC from cancer-free controls and also accurately discriminated PaC patients from chronic pancreatitis (CP) patients. Among the 7 miRNAs, miR-21 levels in serum were significantly associated with overall PaC survival. The diagnostic accuracy rate of the 7-miRNA profile was 83.6% in correctly classifying 55 cases with clinically suspected PaC. CONCLUSIONS: These data demonstrate that the 7 miRNA-based biomarker can serve as a novel noninvasive approach for PaC diagnosis and prognosis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22114139,"Year":2012,"Title":"MicroRNA alterations of pancreatic intraepithelial neoplasias.","Abstract":"PURPOSE: MicroRNA (miRNA) alterations are likely to contribute to the development of pancreatic cancer and may serve as markers for the early detection of pancreatic neoplasia. EXPERIMENTAL DESIGN: To identify the miRNA alterations that arise during the development of pancreatic cancer, we determined the levels of 735 miRNAs in 34 pancreatic intraepithelial neoplasias (PanIN) and 15 normal pancreatic duct samples isolated by laser capture microdissection using TaqMan miRNA microarrays. Differential expression of selected miRNAs was confirmed by FISH analysis and by quantitative real-time reverse transcription PCR (qRT-PCR) analysis of selected candidate miRNAs in an independent set of PanIN and normal duct samples. RESULTS: We identified 107 aberrantly expressed miRNAs in different PanIN grades compared with normal pancreatic duct samples and 35 aberrantly expressed miRNAs in PanIN-3 lesions compared with normal pancreatic duct samples. These differentially expressed miRNAs included those that have been previously identified as differentially expressed in pancreatic ductal adenocarcinomas (PDAC; including miR-21, miR-200a/b/c, miR-216a/b, miR-217, miR-146a, miR-155, miR-182, miR-196b, miR-203, miR-222, miR-338-3p, miR-486-3p, etc.) as well as miRNAs not previously described as differentially expressed in these lesions (miR-125b, miR-296-5p, miR-183*, miR-603, miR-625/*, miR-708, etc.). miR-196b was the most selectively differentially expressed miRNA in PanIN-3 lesions. CONCLUSIONS: Many miRNAs undergo aberrant expression in PanIN lesions and are likely to be important in the development of PDAC. The miRNAs, such as miR-196b, whose expression is limited to PanIN-3 lesions or pancreatic cancers could be useful as diagnostic markers.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22114136,"Year":2012,"Title":"MicroRNA molecular profiles associated with diagnosis, clinicopathologic criteria, and overall survival in patients with resectable pancreatic ductal adenocarcinoma.","Abstract":"PURPOSE: MicroRNAs (miRNA) have potential as diagnostic and prognostic biomarkers and as therapeutic targets in cancer. We sought to establish the relationship between miRNA expression and clinicopathologic parameters, including prognosis, in pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Global miRNA microarray expression profiling of prospectively collected fresh-frozen PDAC tissue was done on an initial test cohort of 48 patients, who had undergone pancreaticoduodenectomy between 2003 and 2008 at a single institution. We evaluated association with tumor stage, lymph node status, and site of recurrence, in addition to overall survival, using Cox regression multivariate analysis. Validation of selected potentially prognostic miRNAs was done in a separate cohort of 24 patients. RESULTS: miRNA profiling identified expression signatures associated with PDAC, lymph node involvement, high tumor grade, and 20 miRNAs were associated with overall survival. In the initial cohort of 48 PDAC patients, high expression of miR-21 (HR = 3.22, 95% CI: 1.21-8.58) and reduced expression of miR-34a (HR = 0.15, 95% CI: 0.06-0.37) and miR-30d (HR = 0.30, 95% CI: 0.12-0.79) were associated with poor overall survival following resection independent of clinical covariates. In a further validation set of 24 patients, miR-21 and miR-34a expression again significantly correlated with overall survival (P = 0.031 and P = 0.001). CONCLUSION: Expression patterns of miRNAs are significantly altered in PDAC. Aberrant expression of a number of miRNAs was independently associated with reduced survival, including overexpression of miR-21 and underexpression of miR-34a. SUMMARY: miRNA expression profiles for resected PDAC were examined to identify potentially prognostic miRNAs. miRNA microarray analysis identified statistically unique profiles, which could discriminate PDAC from paired nonmalignant pancreatic tissues as well as molecular signatures that differ according to pathologic features. miRNA expression profiles correlated with overall survival of PDAC following resection, indicating that miRNAs provide prognostic utility.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":22064652,"Year":2012,"Title":"MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADAM9.","Abstract":"The epithelial-mesenchymal transition (EMT) is a critical step for pancreatic cancer cells as an entry of metastatic disease. Wide variety of cytokines and signaling pathways are involved in this complex process while the entire picture is still cryptic. Recently, miRNA was found to regulate cellular function including EMT by targeting multiple mRNAs. We conducted comprehensive analysis of miRNA expression profiles in invasive ductal adenocarcinoma (IDA), intraductal papillary mucinous adenoma, intraductal papillary mucinous carcinoma, and human pancreatic cancer cell line to elucidate essential miRNAs which regulate invasive growth of pancreatic cancer cells. Along with higher expression of miR-21 which has been shown to be highly expressed in IDA, reduced expression of miR-126 in IDA and pancreatic cancer cell line was detected. The miR-126 was found to target ADAM9 (disintegrin and metalloproteinase domain-containing protein 9) which is highly expressed in pancreatic cancer. The direct interaction between miR-126 and ADAM9 mRNA was confirmed by 3' untranslated region assay. Reexpression of miR-126 and siRNA-based knockdown of ADAM9 in pancreatic cancer cells resulted in reduced cellular migration, invasion, and induction of epithelial marker E-cadherin. We showed for the first time that the miR-126/ADAM9 axis plays essential role in the inhibition of invasive growth of pancreatic cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21983937,"Year":2012,"Title":"Association of microRNA-21 expression with its targets, PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma.","Abstract":"Since the discovery of small non-coding RNAs, the analyses of microRNA (miRNA) expression patterns in human cancer have provided new insights into cancer biology. miRNA-21 has been suggested to be one of the miRNAs that have an important role in the development or biological behavior of a variety of malignancies, including pancreatic cancer. This study was conducted to evaluate the relationship between the expression of miRNA-21 and that of its molecular targets, programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinase (TIMP3), in pancreatic ductal adenocarcinoma. The study included 65 pancreatic ductal adenocarcinomas and 5 normal pancreatic tissue specimens for comparison. The miRNA expression profiling of five selected pancreatic ductal adenocarcinomas and five normal pancreatic specimens was performed using a microarray platform, and was evaluated by a hierarchical clustering analysis. The miRNA most highly expressed in pancreatic ductal adenocarcinomas (ie, miRNA-21) was further assessed by quantitative real-time reverse transcription PCR (RT-PCR) assays in the 65 pancreatic ductal adenocarcinoma cases. The expression pattern of its molecular targets (eg, PDCD4 and TIMP3) in pancreatic ductal adenocarcinoma was examined immunohistochemically. In the microarray analyses, 28 miRNAs were upregulated in pancreatic ductal adenocarcinoma compared with normal pancreatic tissue, whereas 48 miRNAs were downregulated. miRNA-21 was the most significantly overexpressed miRNA in the pancreatic ductal adenocarcinomas analyzed, and was also highly expressed in 75% of the 65 pancreatic ductal adenocarcinomas examined by real-time RT-PCR. High miRNA-21 expression was correlated with a worse prognosis in the pancreatic ductal adenocarcinoma patients (P=0.045). The immunohistochemical expression patterns of PDCD4 (reduced nuclear staining pattern) and TIMP3 (downregulated expression) were significantly associated with both the upregulated miR-21 expression (P<0.05) and the poor survival of the patients (P<0.001 and P=0.001, respectively). Our data suggest that an overexpression of miRNA-21 is, therefore, associated with the biological behavior of pancreatic ductal adenocarcinoma via the downregulation of the expression of tumor suppressors, PDCD4 and TIMP3, thus resulting in tumor progression and the adverse clinical course of pancreatic ductal adenocarcinoma.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21913185,"Year":2012,"Title":"Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer.","Abstract":"This study was performed to identify plasma microRNAs (miRNAs) as diagnostic biomarkers for pancreatic cancer (PCa) and to assess their supplementary role with serum CA19-9 in early identification of tumors. Plasma RNAs were extracted from 140 PCa patients, 111 chronic pancreatitis (CP) patients and 68 normal controls, and the relative abundances of seven miRNAs (miR-16, 21, 155, 181a, 181b, 196a and 210) were measured using real-time PCR. Their diagnostic utility for PCa and correlation with clinical characteristics were analyzed. All seven miRNAs were significantly aberrantly upregulated in the PCa group compared with both the CP and normal groups, between which only four miRNAs (miR-155, 181a, 181b and 196a) were significantly different. Logistic modeling proved that only miR-16 and miR-196a possessed an independent role in discriminating PCa from normal and CP. Furthermore, after including serum CA19-9 in the logistic model, the combination of miR-16, miR-196a and CA19-9 was more effective for discriminating PCa from non-PCa (normal+CP) (AUC-ROC, 0.979; sensitivity, 92.0%; specificity, 95.6%), and for discriminating PCa from CP (AUC-ROC, 0.956; sensitivity, 88.4%; specificity, 96.3%) compared with the miRNA panel (miR-16+miR-196a) or CA19-9 alone. Most significantly, the combination was effective at identification of tumors in Stage 1 (85.2%). In conclusion, plasma miRNAs were effective for distinguishing PCa from non-PCa (normal+CP). The combination of miR-16, miR-196a and CA19-9 was more effective for PCa diagnosis, especially in early tumor screening.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21882851,"Year":2012,"Title":"Genomic profiling of microRNAs and proteomics reveals an early molecular alteration associated with tumorigenesis induced by MC-LR in mice.","Abstract":"Studies have demonstrated that microcystins (MCs) can act as potential carcinogens and have caused serious risk to public environmental health. The molecular mechanisms of MC-induced susceptibility to carcinogenesis are largely unknown. In this study, we performed for the first time a comprehensive analysis of changes in microRNAs (miRNAs) and proteins expression in livers of mice treated with MC-LR. Utilizing microarray and two-dimensional gel electrophoresis (2-DE) analysis, we identified 37 miRNAs and 42 proteins significantly altered. Many aberrantly expressed miRNAs were related to various cancers (e.g., miR-125b, hepatocellular carcinoma; miR-21, leukemia; miR-16, chronic lymphocytic leukemia; miR-192, pituitary adenomas; miR-199a-3p, ovarian cancer; miR-34a, pancreatic cancer). Several miRNAs (e.g., miR-34a, miR-21) and proteins (e.g., TGM2, NDRG2) that play crucial roles in liver tumorigenesis were first found to be affected by MC-LR in mouse liver. MC-LR also altered the expression of a number of miRNAs and proteins involved in several pathways related to tumorigenesis, such as glutathione metabolism, VEGF signaling, and MAPK signaling pathway. Integration of post-transcriptomics, proteomics, and transcriptomics reveals that the networks miRNAs and their potential target genes and proteins involved in had a close association with carcinogenesis. These results provide an early molecular mechanism for liver tumorigenesis induced by MCs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21826251,"Year":2011,"Title":"Holoclone forming cells from pancreatic cancer cells enrich tumor initiating cells and represent a novel model for study of cancer stem cells.","Abstract":"BACKGROUND: Pancreatic cancer is one of the direct causes of cancer-related death. High level of chemoresistance is one of the major obstacles of clinical treatment. In recent years, cancer stem cells have been widely identified and indicated as the origin of chemoresistance in multi-types of solid tumors. Increasing evidences suggest that cancer stem cells reside in the cells capable of forming holoclones continuously. However, in pancreatic cancer, holoclone-forming cells have not been characterized yet. Therefore, the goal of our present study was to indentify the holoclone-forming pancreatic cancer stem cells and develop an in vitro continuous colony formation system, which will greatly facilitate the study of pancreatic cancer stem cells. METHODOLOGY/PRINCIPAL FINDINGS: Pancreatic cancer cell line BxPC3 was submitted to monoclonal cultivation to generate colonies. Based on the morphologies, colonies were classified and analyzed for their capacities of secondary colony formation, long-term survival in vitro, tumor formation in vivo, and drug resistance. Flowcytometry and quantitative RT-PCR were performed to detect the expression level of cancer stem cells associated cell surface markers, regulatory genes and microRNAs in distinct types of colonies. Three types of colonies with distinct morphologies were identified and termed as holo-, mero-, and paraclones, in which only holoclones generated descendant colonies of all three types in further passages. Compared to mero- and paraclones, holoclones possessed higher capacities of long-term survival, tumor initiation, and chemoresistance. The preferential expression of cancer stem cells related marker (CXCR4), regulatory genes (BMI1, GLI1, and GLI2) and microRNAs (miR-214, miR-21, miR-221, miR-222 and miR-155) in holoclones were also highlighted. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the pancreatic tumor-initiating cells with high level of chemoresistance were enriched in holoclones derived from BxPC3 cell line. Generation of holoclones can serve as a novel model for studying cancer stem cells, and attribute to developing new anti-cancer drugs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21757972,"Year":2011,"Title":"Elevated microRNA miR-21 levels in pancreatic cyst fluid are predictive of mucinous precursor lesions of ductal adenocarcinoma.","Abstract":"BACKGROUND: Biomarkers for the diagnostic classification of pancreatic cysts are urgently needed. Deregulated microRNA (miRNAs) expression is widespread in pancreatic cancer. We assessed whether aberrant miRNAs in pancreatic cyst fluid could be used as potential biomarkers for cystic precursor lesions of pancreatic cancer. METHODS: Cyst fluid specimens were prospectively collected from 40 surgically resected pancreatic cysts, and small RNAs were extracted. The 'mucinous' cohort included 14 intraductal papillary mucinous neoplasms (including 3 with an associated adenocarcinoma) and 10 mucinous cystic neoplasms; the 'nonmucinous' cohort included 11 serous cystadenomas and 5 other benign cysts. Quantitative reverse transcription PCR was performed for five miRNAs (miR-21, miR-155, miR-221, miR-17-3p, miR-191), which were previously reported as overexpressed in pancreatic adenocarcinomas. RESULTS: Significantly higher expression of miR-21, miR-221, and miR-17-3p was observed in the mucinous versus nonmucinous cysts (p < 0.01), with the mean relative fold differences being 7.0-, 7.9-, and 5.4-fold, respectively. Receiver operating characteristic curves demonstrated the highest median area under the curve for miR-21, with a median specificity of 76%, at a sensitivity of 80%. CONCLUSION: This pilot study demonstrates that profiling miRNAs in pancreatic cyst fluid samples is feasible and can yield potential biomarkers for the classification of cystic lesions of the pancreas. and IAP.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21743960,"Year":2011,"Title":"Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer.","Abstract":"The presence of tumor cells in the bone marrow (BM) could be relevant to identifying high risk of disease progression and death in gastrointestinal cancer. However, the molecular profile associated with disseminated tumor cells (DTCs) homing to the BM has yet to be defined. MicroRNAs (miRNA) play key roles in cellular processes implicated in cancer. Thus, we investigated in 38 patients with colorectal, gastric or pancreatic cancer whether the presence of BM-DTCs is associated with a specific miRNA tumor profile and analyzed their potential prognostic impact. DTCs were detected by immunocytochemistry and anti-cytokeratin antibodies in 42.1% of the patients. miRNAs were isolated from formalin-fixed, paraffin-embedded tumors. qRT-PCR was used for miRNA profiling. No significant associations were found among DTC detection and miRNA deregulation. Kaplan-Meier curves demonstrated significantly reduced progression-free survival (PFS) and overall survival (OS) in the DTC-positive patients. Although miR-21 was upregulated in 90.6% of the tumors, no associations with outcomes were found. miR-17 and miR-20a (miRNA-17-92 cluster) were upregulated in 33.3 and 42.4%, respectively. Upregulation of both was correlated and found in 30.3%. Univariate analysis shows that increasing values for miR-20a were significantly associated with reduced PFS (HR 1.022; p=0.016) and OS (HR 1.027; p=0.003). In multivariate Cox models, DTC positivity (HR 4.07; p=0.005) and miR-17 overexpression (HR 2.11; p=0.003) were significantly associated with a higher risk of disease progression. The presence of DTCs in the BM (HR 3.98; p=0.010) and a miR-17 overexpression (HR 2.62; p<0.001) were also associated with a risk of death. Our study suggests that the presence of BM-DTCs and the upregulation of the miR-17-92 cluster in tumors are both significant but independent prognostic markers in gastrointestinal cancer patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21738581,"Year":2011,"Title":"Tissue and serum microRNAs in the Kras(G12D) transgenic animal model and in patients with pancreatic cancer.","Abstract":"microRNAs (miRs) modulate the expression levels of mRNAs and proteins and can thus contribute to cancer initiation and progression. In addition to their intracelluar function, miRs are released from cells and shed into the circulation. We postulated that circulating miRs could provide insight into pathways altered during cancer progression and may indicate responses to treatment. Here we focus on pancreatic cancer malignant progression. We report that changes in miR expression patterns during progression of normal tissues to invasive pancreatic adenocarcinoma in the p48-Cre/LSL-Kras(G12D) mouse model mirrors the miR changes observed in human pancreatic cancer tissues. miR-148a/b and miR-375 expression were found decreased whereas miR-10, miR-21, miR-100 and miR-155 were increased when comparing normal tissues, premalignant lesions and invasive carcinoma in the mouse model. Predicted target mRNAs FGFR1 (miR-10) and MLH1 (miR-155) were found downregulated. Quantitation of nine microRNAs in plasma samples from patients distinguished pancreatic cancers from other cancers as well as non-cancerous pancreatic disease. Finally, gemcitabine treatment of control animals and p48-Cre/LSL-Kras(G12D) animals with pancreatic cancer caused distinct and up to 60-fold changes in circulating miRs that indicate differential drug effects on normal and cancer tissues. These findings support the significance of detecting miRs in the circulation and suggests that circulating miRs could serve as indicators of drug response.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21652542,"Year":2011,"Title":"MicroRNA-10b expression correlates with response to neoadjuvant therapy and survival in pancreatic ductal adenocarcinoma.","Abstract":"INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Diagnosis and management of PDAC are hampered by the absence of sensitive and specific disease biomarkers. MicroRNAs (miRNA) are noncoding regulatory RNAs involved in initiation and progression of human cancers. In this study, we sought to determine whether miR-10b could serve as a biomarker for PDAC. EXPERIMENTAL DESIGN: miRNA expression was characterized by fluorescence-based in situ hybridization using locked nucleic acid-modified DNA probes against miR-10b, miR-21, miR-155, miR-196a, and miR-210, followed by codetection of proteins by immunohistochemistry on the same tissue sections. miRNA expression in surgically resected PDAC tissues and in endoscopic ultrasonography (EUS)-guided fine-needle aspirate (EUS-FNA) samples was analyzed in cytokeratin 19 (CK19)-positive epithelial cells using optical intensity analysis. RESULTS: In 10 resected PDAC samples, miR-10b was the most frequently and consistently overexpressed miRNA among characterized miRNAs, exhibiting a four-fold increase in the cancer cells (P = 0.012). Given this preferential overexpression of miR-10b, we sought to determine whether miR-10b expression was clinically relevant. Accordingly, miR-10b expression was examined in 106 EUS-FNA samples obtained from pancreatic lesions. miR-10b expression was increased in cancer cells compared with CK19-positive epithelial cells in benign lesions (P = 0.0001). In patients with PDACs, lower levels of miR-10b were associated with improved response to multimodality neoadjuvant therapy, likelihood of surgical resection, delayed time to metastasis, and increased survival. CONCLUSION: miR-10b is a novel diagnostic biomarker for PDACs when assessing pancreatic lesions. Expression of miR-10b is predictive of response to neoadjuvant therapy and outcome in this disease.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21463919,"Year":2011,"Title":"Notch-1 induces epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells.","Abstract":"Activation of Notch-1 is known to be associated with the development and progression of human malignancies including pancreatic cancer. Emerging evidence suggest that the acquisition of epithelial-mesenchymal transition (EMT) phenotype and induction of cancer stem cell (CSC) or cancer stem-like cell phenotype are interrelated and contributes to tumor recurrence and drug resistance. The molecular mechanism(s) by which Notch-1 contributes to the acquisition of EMT phenotype and CSC self-renewal capacity has not been fully elucidated. Here we show that forced over-expression of Notch-1 leads to increased cell growth, clonogenicity, migration and invasion of AsPC-1 cells. Moreover, over-expression of Notch-1 led to the induction of EMT phenotype by activation of mesenchymal cell markers such as ZEB1, CD44, EpCAM, and Hes-1. Here we also report, for the first time, that over-expression of Notch-1 leads to increased expression of miR-21, and decreased expression of miR-200b, miR-200c, let-7a, let-7b, and let-7c. Re-expression of miR-200b led to decreased expression of ZEB1, and vimentin, and increased expression of E-cadherin. Over-expression of Notch-1 also increased the formation of pancreatospheres consistent with expression of CSC surface markers CD44 and EpCAM. Finally, we found that genistein, a known natural anti-tumor agent inhibited cell growth, clonogenicity, migration, invasion, EMT phenotype, formation of pancreatospheres and expression of CD44 and EpCAM. These results suggest that the activation of Notch-1 signaling contributes to the acquisition of EMT phenotype, which is in part mediated through the regulation of miR-200b and CSC self-renewal capacity, and these processes could be attenuated by genistein treatment.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21408027,"Year":2011,"Title":"Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer.","Abstract":"BACKGROUND: The existence of cancer stem cells (CSCs) or cancer stem-like cells in a tumor mass is believed to be responsible for tumor recurrence because of their intrinsic and extrinsic drug-resistance characteristics. Therefore, targeted killing of CSCs would be a newer strategy for the prevention of tumor recurrence and/or treatment by overcoming drug-resistance. We have developed a novel synthetic compound-CDF, which showed greater bioavailability in animal tissues such as pancreas, and also induced cell growth inhibition and apoptosis, which was mediated by inactivation of NF-kappaB, COX-2, and VEGF in pancreatic cancer (PC) cells. METHODOLOGY/PRINCIPAL FINDINGS: In the current study we showed, for the first time, that CDF could significantly inhibit the sphere-forming ability (pancreatospheres) of PC cells consistent with increased disintegration of pancreatospheres, which was associated with attenuation of CSC markers (CD44 and EpCAM), especially in gemcitabine-resistant (MIAPaCa-2) PC cells containing high proportion of CSCs consistent with increased miR-21 and decreased miR-200. In a xenograft mouse model of human PC, CDF treatment significantly inhibited tumor growth, which was associated with decreased NF-kappaB DNA binding activity, COX-2, and miR-21 expression, and increased PTEN and miR-200 expression in tumor remnants. CONCLUSIONS/SIGNIFICANCE: These results strongly suggest that the anti-tumor activity of CDF is associated with inhibition of CSC function via down-regulation of CSC-associated signaling pathways. Therefore, CDF could be useful for the prevention of tumor recurrence and/or treatment of PC with better treatment outcome in the future.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21376256,"Year":2011,"Title":"Bcl-2 upregulation induced by miR-21 via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells.","Abstract":"BACKGROUND AND AIMS: Bcl-2 was previously shown to be associated with apoptosis and chemoresistance and carry multiple regulating pathways. However, the roles and mechanisms of miRNA (miR)-21 in regulation of Bcl-2 in pancreatic cancer remain to be elucidated. The aim of this study was to explore the regulation of Bcl-2 expression by miR-21 and its impact on apoptosis, chemoresistance and growth of pancreatic cancer cells using a pancreatic cancer cell line, MIA PaCa-2. METHODS: miR-21 mimics and inhibitor were transfected to MIA PaCa-2 pancreatic cancer cells, respectively. Alteration in Bcl-2/Bax expression was subsequently evaluated. Then, luciferase activity was observed after miR-21 mimics and pRL-TK plasmids containing wild-type and mutant 3'UTRs of Bcl-2 mRNA were co-transfected. Finally, apoptosis, chemosensitivity to gemcitabine and cell proliferation were evaluated. RESULTS: Upregulation of Bcl-2 expression was detected in cells transfected with miR-21 mimics, accompanied by downregulated Bax expression, less apoptosis, lower caspase-3 activity, decreased chemosensitivity to gemcitabine and increased proliferation compared with the control cells. Cells transfected with miR-21 inhibitor revealed an opposite trend. There was a significant increase in luciferase activity in the cells transfected with the wild-type pRL-TK plasmid, in contrast to those transfected with the mutant one, indicating that miR-21 promotes Bcl-2 expression by binding directly to the 3'UTR of Bcl-2 mRNA. CONCLUSIONS: Upregulation of Bcl-2 directly induced by miR-21 is associated with apoptosis, chemoresistance and proliferation of MIA PaCa-2 pancreatic cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21139804,"Year":2010,"Title":"Differentially expressed miRNAs in the plasma may provide a molecular signature for aggressive pancreatic cancer.","Abstract":"Pancreatic cancer (PC) has the poorest overall survival rate among all human cancers because of late diagnosis and absence of screening tools. We compared the expression profile of microRNAs (miRNAs) in the plasma of patients diagnosed with PC (n=50) with healthy volunteers (n=10). Data was further validated by quantitative realtime PCR and cell-based assays. Thirty-seven miRNAs were down-regulated and 54 were up-regulated in plasma from patients with PC. The expression of miR-21 was significantly higher, and the expression of let-7 family (especially let-7d) and miR-146a was significantly lower in PC. Most interestingly, the expression of miR-21 was correlated with worse survival, and the expression of let-7 was inversely correlated with survival in this pilot study with mixed patient population. Moreover, we found that miR-21 family was markedly over-expressed in chemo-resistant PC cell lines, which was consistent with the plasma data from PC patients. Our previous studies have shown increased expression of miR-21 with concomitant loss of PTEN expression in PC cells, which is consistent with our current findings showing the loss of three additional targets of miR-21 (PDCD4, Maspin and TPM1). These results suggest that identifying and validating the expression of miRNAs in newly diagnosed patients could serve as potential biomarker for tumor aggressiveness, and such miRNAs could be useful for the screening of high-risk patients, and may also serve as targets for future drug development.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21088996,"Year":2011,"Title":"Knockdown of microRNA-21 inhibits proliferation and increases cell death by targeting programmed cell death 4 (PDCD4) in pancreatic ductal adenocarcinoma.","Abstract":"OBJECTIVE: This study aims to examine the expression of a panel of five microRNAs (miRNA) in pancreatic ductal adenocarcinoma (PDAC) and the functional effect of miR-21 inhibition in PDAC cell lines. BACKGROUND: miRNA are short, non-coding RNA molecules, which play important roles in several cellular processes by silencing expression of their target genes through translational repression or mRNA degradation. They are often aberrantly expressed in cancer, and this dysregulation can promote carcinogenesis by altering the expression of tumour suppressor or oncogenes. METHODS: miRNA expression levels were measured in 24 PDAC tumour/matched adjacent normal tissue samples and three PDAC cell lines using reverse transcription polymerase chain reaction. Levels of cell proliferation and death and expression of programmed cell death 4 (PDCD4; tumour suppressor) were studied in PDAC cells (MIA-Pa-Ca-2) in the absence or presence of a miR-21 inhibitor. RESULTS: PDAC primary tissues and cell lines displayed a consistent upregulation of miR-21 (P < 0.0001) and downregulation of both miR-148a (P < 0.0001) and miR-375 (P < 0.0001) relative to adjacent normal tissue. Furthermore, miR-21 levels in the primary tumours correlated with disease stage (P < 0.0001). Inhibition of miR-21 in MIA-Pa-Ca-2 PDAC cells led to reduced cell proliferation (P < 0.01) and increased cell death (P < 0.01), with simultaneous increase in levels of the tumour suppressor, PDCD4 (P < 0.01). CONCLUSION: miRNA expression profiles may be used as biomarkers for detecting pancreatic cancer. Moreover, miR-21 could be a predictor of disease progression and a possible therapeutic target in part by upregulating PDCD4 in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":21068491,"Year":2010,"Title":"MicroRNA expression analyses in preoperative pancreatic juice samples of pancreatic ductal adenocarcinoma.","Abstract":"CONTEXT: Cytological assessment of pancreatic juice is commonly used to diagnose pancreatic ductal adenocarcinoma; however, the sensitivity of cytological assessment has been reported to be low. MicroRNAs are small RNAs regulating various cellular processes and have recently been identified as possible markers of malignant diseases including pancreatic ductal adenocarcinoma. OBJECTIVE: The purposes of this study were to prove the existence of microRNAs in pancreatic juice and to determine whether specific microRNAs in pancreatic juice could be used for detecting pancreatic ductal adenocarcinoma. METHODS: Relative expression levels of microRNA-21 and microRNA-155 in formalin-fixed paraffin-embedded tissues of resected specimens (no. 13) and pancreatic juice samples collected using preoperative endoscopic retrograde cholangiopancreatography (no. 21) were quantified and their expression levels were then compared to pancreatic ductal adenocarcinoma and chronic pancreatitis. RESULTS: Relative expression levels of microRNA-21 in tissue and pancreatic juice samples were significantly higher in pancreatic ductal adenocarcinoma than those in chronic pancreatitis (P=0.009 and P=0.021, respectively). The same results were obtained in the expression levels of microRNA-155 in tissue and pancreatic juice between pancreatic ductal adenocarcinoma and chronic pancreatitis (P=0.014 and P=0.021, respectively). Expression levels of microRNA-21 and microRNA-155 did not correlate with the preoperative cytological results of pancreatic juice. CONCLUSION: MicroRNA-21 and microRNA-155 in pancreatic juice have the potential of becoming biomarkers for diagnosing pancreatic ductal adenocarcinoma.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":20614181,"Year":2011,"Title":"Detection of differentially expressed microRNAs in serum of pancreatic ductal adenocarcinoma patients: miR-196a could be a potential marker for poor prognosis.","Abstract":"BACKGROUND: MicroRNAs (miRNAs) have long been established to remain stable in circulation, and dysregulated miRNAs in serum of tumor patients could potentially serve as novel biomarkers. AIMS: To determine whether certain serum miRNAs could represent potential diagnostic and prognostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). METHODS: About 35 patients diagnosed with PDAC at different stages between August 2007 and January 2009 were enrolled in this study. Sera from 15 chronic pancreatitis (CP) patients and 15 healthy individuals were treated as controls. Quantitative real-time polymerase chain reaction assays specific to mature miRNAs were used to quantify the relative levels of those PDAC-associated serum miRNAs. RESULTS: Of the seven miRNAs detected, three were identified as differentially expressed in PDAC and control groups. miR-21 was able to distinguish PDAC patients from CP (p = 0.033) and healthy subjects (p = 0.001), whereas miR-155 and miR-196a were able to differentiate sera with sick pancreas (PDAC/CP) from normal pancreas (p = 0.0002 and 0.010, respectively). Serum miR-196a expression levels in unresectable PDAC (stages III and IV) patients were significantly higher than those in resectable (stages I and II) patients (p = 0.001). Furthermore, serum miR-196a expression level was found to have a potential value in predicting median survival time of PDAC patients (high-level miR-196a, 6.1 months, (95% CI, 4.49-7.72) versus low-level miR-196a, 12.00 months, (95% CI, 5.92-18.08), p = 0.007). CONCLUSIONS: Serum miR-196a could be a potential noninvasive marker for PDAC prognosis and selection of laparotomy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":20498843,"Year":2010,"Title":"Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer.","Abstract":"BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. The high risk of recurrence following surgical resection provides the rationale for adjuvant therapy. However, only a subset of patients benefit from adjuvant therapy. Identification of molecular markers to predict treatment outcome is therefore warranted. The aim of the present study was to evaluate whether expression of novel candidate biomarkers, including microRNAs, can predict clinical outcome in PDAC patients treated with adjuvant therapy. METHODOLOGY/PRINCIPAL FINDINGS: Formalin-fixed paraffin embedded specimens from a cohort of 82 resected Korean PDAC cases were analyzed for protein expression by immunohistochemistry and for microRNA expression using quantitative Real-Time PCR. Cox proportional hazards model analysis in the subgroup of patients treated with adjuvant therapy (N = 52) showed that lower than median miR-21 expression was associated with a significantly lower hazard ratio (HR) for death (HR = 0.316; 95%CI = 0.166-0.600; P = 0.0004) and recurrence (HR = 0.521; 95%CI = 0.280-0.967; P = 0.04). MiR-21 expression status emerged as the single most predictive biomarker for treatment outcome among all 27 biological and 9 clinicopathological factors evaluated. No significant association was detected in patients not treated with adjuvant therapy. In an independent validation cohort of 45 frozen PDAC tissues from Italian cases, all treated with adjuvant therapy, lower than median miR-21 expression was confirmed to be correlated with longer overall as well as disease-free survival. Furthermore, transfection with anti-miR-21 enhanced the chemosensitivity of PDAC cells. CONCLUSIONS SIGNIFICANCE: Low miR-21 expression was associated with benefit from adjuvant treatment in two independent cohorts of PDAC cases, and anti-miR-21 increased anticancer drug activity in vitro. These data provide evidence that miR-21 may allow stratification for adjuvant therapy, and represents a new potential target for therapy in PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":20460539,"Year":2010,"Title":"MicroRNA-21 in pancreatic cancer: correlation with clinical outcome and pharmacologic aspects underlying its role in the modulation of gemcitabine activity.","Abstract":"MicroRNA-21 (miR-21) was reported to be overexpressed and contributes to invasion and gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to evaluate whether miR-21 expression was associated with the overall survival (OS) of PDAC patients treated with gemcitabine and to provide mechanistic insights for new therapeutic targets. miR-21 expression was evaluated in cells (including 7 PDAC cell lines, 7 primary cultures, fibroblasts, and a normal pancreatic ductal cell line) and tissues (neoplastic specimens from 81 PDAC patients and normal ductal samples) isolated by laser microdissection. The role of miR-21 on the pharmacologic effects of gemcitabine was studied with a specific miR-21 precursor (pre-miR-21). Patients with high miR-21 expression had a significantly shorter OS both in the metastatic and in the adjuvant setting. Multivariate analysis confirmed the prognostic significance of miR-21. miR-21 expression in primary cultures correlated with expression in their respective tissues and with gemcitabine resistance. Pre-miR-21 transfection significantly decreased antiproliferative effects and apoptosis induction by gemcitabine, whereas matrix metalloproteinase (MMP)-2/MMP-9 and vascular endothelial growth factor expression were upregulated. Addition of inhibitors of phosphoinositide 3-kinase and mammalian target of rapamycin resulted in decrease of phospho-Akt and prevented pre-miR-21-induced resistance to the proapoptotic effects of gemcitabine. miR-21 expression correlated with outcome in PDAC patients treated with gemcitabine. Modulation of apoptosis, Akt phosphorylation, and expression of genes involved in invasive behavior may contribute to the role of miR-21 in gemcitabine chemoresistance and to the rational development of new targeted combinations.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":20388782,"Year":2010,"Title":"Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF.","Abstract":"Curcumin induces cancer cell growth arrest and apoptosis in vitro, but its poor bioavailability in vivo limits its antitumor efficacy. We have previously evaluated the bioavailability of novel analogues of curcumin compared with curcumin, and we found that the analogue CDF exhibited greater systemic and pancreatic tissue bioavailability. In this study, we evaluated the effects of CDF or curcumin alone or in combination with gemcitabine on cell viability and apoptosis in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer (PC) cell lines. Mechanistic investigations revealed a significant reduction in cell viability in CDF-treated cells compared with curcumin-treated cells, which were also associated with the induction of apoptosis, and these results were consistent with the downregulation of Akt, cyclooxygenase-2, prostaglandin E(2), vascular endothelial growth factor, and NF-kappaB DNA binding activity. We have also documented attenuated expression of miR-200 and increased expression of miR-21 (a signature of tumor aggressiveness) in gemcitabine-resistant cells relative to gemcitabine-sensitive cells. Interestingly, CDF treatment upregulated miR-200 expression and downregulated the expression of miR-21, and the downregulation of miR-21 resulted in the induction of PTEN. These results prompt further interest in CDF as a drug modality to improve treatment outcome of patients diagnosed with PC as a result of its greater bioavailability in pancreatic tissue.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":20332664,"Year":2010,"Title":"Aberrant MicroRNA-155 expression is an early event in the multistep progression of pancreatic adenocarcinoma.","Abstract":"BACKGROUND/AIMS: Pancreatic intraepithelial neoplasia (PanIN) is the most common noninvasive precursor to invasive pancreatic adenocarcinoma. Misexpression of microRNAs (miRNAs) is commonly encountered in invasive neoplasia; however, miRNA abnormalities in PanIN lesions have not been documented. METHODS: Three candidate miRNAs (miR-21, miR-155, and miR-221) previously reported as overexpressed in pancreatic cancers were assessed in 31 microdissected PanINs (14 PanIN-1, 9 PanIN-2, 8 PanIN-3) using quantitative reverse transcription PCR (qRT-PCR). Subsequently, miR-155 was evaluated by locked nucleic acid in situ hybridization (LNA-ISH) in PanIN tissue microarrays. RESULTS: Relative to microdissected non-neoplastic ductal epithelium, significant overexpression of miR-155 was observed in both PanIN-2 (2.6-fold, p = 0.02) and in PanIN-3 (7.4-fold, p = 0.014), while borderline significant overexpression of miR-21 (2.5-fold, p = 0.049) was observed in PanIN-3 only. In contrast, no significant differences in miR-221 levels were observed between ductal epithelium and PanIN lesions by qRT-PCR. LNA-ISH confirmed the aberrant expression of miR-155 in PanIN-2 (9 of 20, 45%) and in PanIN-3 (8 of 13, 62%), respectively, when compared with normal ductal epithelium (0 of 10) (p < 0.01). CONCLUSIONS: Abnormalities of miRNA expression are observed in the multistep progression of pancreatic cancer, with miR-155 aberrations demonstrable at the stage of PanIN-2, and miR-21 abnormalities at the stage of PanIN-3 lesions. and IAP.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":20093556,"Year":2010,"Title":"MicroRNA-21 is induced early in pancreatic ductal adenocarcinoma precursor lesions.","Abstract":"BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has the poorest overall prognosis among gastrointestinal cancers; however, curative resection in early-stage PDAC greatly improves survival rates, indicating the importance of early detection. Because abnormal microRNA production is commonly detected in cancer, we investigated noninvasive precursor pancreatic intraepithelial neoplasia (PanIN) lesions for microRNA production as a potential early biomarker of PDAC. METHODS: Pathologists identified and classified ductal lesions. We extracted total RNA from laser-capture microdissected PanIN tissue samples from a conditional KRAS(G12D) mouse model (n = 29) or of human origin (n = 38) (KRAS is v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). MicroRNA production was quantified by quantitative real-time PCR. Internal controls included 5S and U6 RNAs. RESULTS: Production of microRNAs miR-21, miR-205, and miR-200 paralleled PanIN progression in the KRAS(G12D) mouse model, compared with microRNA production in samples of nonpathologic ducts. miR-21 demonstrated the highest relative concentrations in the precursor lesions. Interestingly, miR-205 and miR-21 up-regulation preceded phenotypic changes in the ducts. The production of microRNAs miR-21, miR-221, miR-222, and let-7a increased with human PanIN grade, with peak production occurring in hyperplastic PanIN-2/3 lesions. In situ hybridization analysis indicated miR-21 production to be concentrated in pathologic ductal cells. miR-21 production was regulated by KRAS(G12D) and epidermal growth factor receptor in PDAC-derived cell lines. CONCLUSIONS: Aberrant microRNA production is an early event in the development of PanIN. Our findings indicate that miR-21 warrants further investigation as a marker for early detection of PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":19730150,"Year":2009,"Title":"Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma.","Abstract":"OBJECTIVES: The contribution of overexpressed microRNA-21 and -221 (miR-21 and miR-221) to the malignant phenotype was determined by inhibiting these miRNAs using antisense oligonucleotides. METHODS: The effects of antisense to miR-21 and miR-221 on cell proliferation, cell cycle arrest, induction of apoptosis, combinatorial effects with gemcitabine, and effects on target protein levels were studied. RESULTS: Low nanomolar concentrations of both antisense oligonucleotides reduced proliferation of pancreatic cancer cell lines. Reduced proliferation was less pronounced in the normal ductal epithelial cell line human pancreatic Nestin-expressing cell or in pancreatic cancer cell lines exposed to an irrelevant control oligonucleotide. Inhibition of miR-21 and miR-221 increased the amount of apoptosis in HS766T cells by 3- to 6-fold compared with the control oligonucleotide. HS766T cells exposed to miR-21 antisense resulted in cell cycle arrest (G1 phase). Protein levels of tumor suppressor targets of the miRNAs were increased by antisense to miR-21 (PTEN and RECK) and miR-221 (p27). Antisense to miR-21 and miR-221 sensitized the effects of gemcitabine, and the antisense-gemcitabine combinations were synergistic at high fraction affected. CONCLUSIONS: We demonstrate that antisense to miR-21 and miR-221 results in significant cell killing under various conditions and that antisense oligonucleotides targeted to miRNA represents a potential new therapy for pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":19723895,"Year":2009,"Title":"MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease.","Abstract":"Development of minimally invasive biomarker assays for early detection and effective clinical management of pancreatic cancer is urgently needed to reduce high morbidity and mortality associated with this malignancy. We hypothesized that if aberrantly expressing microRNAs (miRNA) in pancreatic adenocarcinoma tissues are detected in blood plasma, then plasma profiling of these miRNAs might serve as a minimally invasive early detection biomarker assay for this malignancy. By using a modified protocol to isolate and quantify plasma miRNAs from heparin-treated blood, we show that miRNA profiling in plasma can differentiate pancreatic adenocarcinoma patients from healthy controls. We have profiled four miRNAs, miR-21, miR-210, miR-155, and miR-196a, all implicated in the development of pancreatic cancer with either proven or predicted target genes involved in critical cancer-associated cellular pathways. Of these, miR-155 has recently been identified as a candidate biomarker of early pancreatic neoplasia, whereas elevated expression of miR196a has been shown to parallel progression of disease. The results revealed a sensitivity of 64% and a specificity of 89% with the analyses of plasma levels for this panel of four miRNAs. The area under the receiver operating characteristic curve were estimated at 0.82 and 0.78 without and with leave-one-out cross-validation scheme, respectively. These observations, although a \"proof of principle\" finding at this time, show the feasibility of developing plasma miRNA profiling as a sensitive and specific blood-based biomarker assay for pancreatic cancer that has the potential of translation to the clinic with additional improvements in the future.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":19435867,"Year":2009,"Title":"MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance.","Abstract":"Due to the poor prognosis of pancreatic cancer, novel diagnostic modalities for early diagnosis and new therapeutic strategy are urgently needed. Recently, microRNA-21 (miR-21) was reported to be strongly overexpressed in pancreatic cancer as well as in other solid cancers. We investigated the functional roles of miR-21, which have not been fully elucidated in pancreatic cancer. miR-21 expression was assessed in pancreatic cancer cell lines (14 cancer cell lines, primary cultures of normal pancreatic epithelial cells and fibroblasts, and a human normal pancreatic ductal epithelial cell line) and pancreatic tissue samples (25 cancer tissues and 25 normal tissues) by quantitative real-time reverse transcription-PCR amplification. Moreover, we investigated the proliferation, invasion, and chemoresistance of pancreatic cancer cells transfected with miR-21 precursor or inhibitor. miR-21 was markedly overexpressed in pancreatic cancer cells compared with nonmalignant cells, and miR-21 in cancer tissues was much higher than in nonmalignant tissues. The cancer cells transfected with the miR-21 precursor showed significantly increased proliferation, Matrigel invasion, and chemoresistance for gemcitabine compared with the control cells. In contrast, inhibition of miR-21 decreased proliferation, Matrigel invasion, and chemoresistance for gemcitabine. Moreover, miR-21 positively correlated with the mRNA expression of invasion-related genes, matrix metalloproteinase-2 and -9, and vascular endothelial growth factor. These data suggest that miR-21 expression is increased in pancreatic cancer cells and that miR-21 contributes to the cell proliferation, invasion, and chemoresistance of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":19430705,"Year":2009,"Title":"Genetic variation of miRNA sequence in pancreatic cancer.","Abstract":"MicroRNAs (miRNAs) are small non-coding RNAs of 20-22 nucleotides (nts) and constitute a novel class of gene regulators that negatively regulate gene expression at the post-transcriptional level. The expression of miRNA is deregulated in many types of cancers. Alterations in miRNA expression may be an important contributor to the development of pancreatic carcinoma. We hypothesized that genetic variations in miRNA genes were associated with pancreatic carcinoma and analyzed genomic sequences coding for the precursors of eight miRNA genes in both pancreatic carcinoma tissues and cancer cell lines. Four novel mutations in primary miRNA transcripts were identified. TaqMan miRNA assays showed that miR-21 was significantly overexpressed in 20 pancreatic carcinomas and 6 cancer cell lines compared with paired benign tissues and normal pancreas. Two mutations of miR-21 did not notably alter the activity of the promoter of the miRNA gene. Although most of these mutations seem to have no effect on miRNA processing, an A-G mutation at 29-nt downstream of pre-miR-21 led to a conformational change of the secondary structure close to the stem reaching into the pre-miR-21 and a relative reduction of the mature miR-21 expression in vivo. These results suggested that miRNA might play an important role in pancreatic tumorigenesis, but the molecular mechanism underlying the particular sequence variations in miRNA that can cause aberrant expression remains to be determined.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":19112422,"Year":2008,"Title":"Effect of trichostatin a on viability and microRNA expression in human pancreatic cancer cell line BxPC-3.","Abstract":"AIM: To investigate the influence of trichostatin A (TSA) on inhibition of cell proliferation and induction of apoptosis in human pancreatic cancer cells. METHODS: MTT-based cytotoxicity assay was used to evaluate the cell viability after treatment with TSA. Cell cycle distribution and apoptosis were examined by means of flow cytometry. Expression of microRNA was determined with microRNA array. Expression of miR-200c and miR-21 was detected by Northern blotting. RESULTS: TSA significantly inhibited the proliferation of BxPC-3 human pancreatic cancer cells in a time- and dose-dependent manner. BxPC-3 cells treated with TSA were arrested in G0/G1 phase and were characterized by increased apoptotic rate, accompanied by differential expression of microRNAs. CONCLUSIONS: The results suggest that TSA may activate expression of microRNAs that may act as tumor suppressor in human pancreatic cancer cell line BxPC-3.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":19106647,"Year":2009,"Title":"MicroRNA miR-155 is a biomarker of early pancreatic neoplasia.","Abstract":"BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions of pancreatic cancer. Misexpression of microRNAs (miRNAs) is commonly observed in pancreatic adenocarcinoma. In contrast, miRNA abnormalities in pancreatic cancer precursor lesions have not been documented. EXPERIMENTAL DESIGN: Relative expression levels of a panel of twelve miRNAs upregulated in pancreatic cancers were assessed in 15 non-invasive IPMNs, using quantitative reverse transcription PCR (qRT-PCR). Two significantly overexpressed miRNAs-miR-155 and miR-21-were evaluated by locked nucleic acid in situ hybridization (LNA-ISH) in a panel of 64 archival IPMNs. The expression of miR-155 and miR-21 was also evaluated in pancreatic juice samples obtained from ten patients with surgically resected IPMNs and five patients with non-neoplastic pancreato-biliary disorders (\"disease controls\"). RESULTS: Significant overexpression by qRT-PCR of ten of the twelve miRNAs was observed in the 15 IPMNs versus matched controls (p < 0.05), with miR-155 (mean 11.6-fold) and miR-21 (mean 12.1-fold) demonstrating highest relative fold-changes in the precursor lesions. LNA-ISH confirmed the expression of miR-155 in 53 of 64 (83%) IPMNs compared to 4 of 54 (7%) normal ducts, and of miR-21 in 52 of 64 (81%) IPMNs compared to 1 of 54 (2%) normal ducts, respectively (p < 0.0001). Upregulation of miR-155 transcripts by qRT-PCR was observed in 6 of 10 (60%) IPMN-associated pancreatic juice samples compared to 0 of 5 (0%) disease controls. CONCLUSIONS: Aberrant miRNA expression is an early event in the multistage progression of pancreatic cancer, and miR-155 warrants further evaluation as a biomarker for IPMNs in clinical samples.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":18642050,"Year":2008,"Title":"MicroRNA-21 is overexpressed in pancreatic cancer and a potential predictor of survival.","Abstract":"BACKGROUND: MicroRNAs are small (18-22 nucleotides) noncoding RNAs involved in posttranscriptional modification of many target genes. One of these, microRNA-21 (miR-21), has been shown to play a role in multiple hematologic and solid organ malignancies. We sought to determine the expression pattern of miR-21 in pancreatic cancers and its impact on clinicopathologic characteristics. METHODS: Eighty resected pancreatic cancer specimens were microdissected and tissue microarrays (TMA) created in duplicate. TMAs were also created for benign pancreas (N = 12) and chronic pancreatitis (N = 45). In situ hybridization (ISH) was undertaken utilizing locked nucleic acid probes for miR-21. RNA U6 and scrambled RNA served as positive and negative control, respectively. ISH was scored as 0 (absent), 1+ (faint/focal expression), or 2+ (strong expression). Kaplan-Meier survival curves were constructed and compared by log-rank analysis. RESULTS: MiR-21 expression was demonstrated in 63 (79%) pancreatic cancers (1+ in 49, 2+ in 14) compared to one of 12 (8%, p < 0.0001) benign pancreas and 12/45 (27%, p < 0.0001) chronic pancreatitis. None of the benign tissues demonstrated strong miR-21 expression. Although miR-21 expression did not correlate with tumor size, differentiation, nodal status, or T stage, strong miR-21 expression was predictive of poorer outcome compared to absent or faint/focal miR-21 expression in patients with node-negative disease (median 27.7 months vs. 15.2, p = 0.037). Nodal status was also predictive of survival (p = 0.029). CONCLUSIONS: MicroRNA-21 is significantly overexpressed in pancreatic cancers as detected by in situ hybridization. Its strong expression predicts limited survival in patients with node-negative disease and may be an important biologic marker for outcome.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":17149698,"Year":2007,"Title":"Expression profiling identifies microRNA signature in pancreatic cancer.","Abstract":"microRNAs are functional, 22 nt, noncoding RNAs that negatively regulate gene expression. Disturbance of microRNA expression may play a role in the initiation and progression of certain diseases. A microRNA expression signature has been identified that is associated with pancreatic cancer. This has been accomplished with the application of real-time PCR profiling of over 200 microRNA precursors on specimens of human pancreatic adenocarcinoma, paired benign tissue, normal pancreas, chronic pancreatitis and nine pancreatic cancer cell lines. Hierarchical clustering was able to distinguish tumor from normal pancreas, pancreatitis and cell lines. The PAM algorithm correctly classified 28 of 28 tumors, 6 of 6 normal pancreas and 11 of 15 adjacent benign tissues. One hundred microRNA precursors were aberrantly expressed in pancreatic cancer or desmoplasia (p < 0.01), including microRNAs previously reported as differentially expressed in other human cancers (miR-155, miR-21, miR-221 and miR-222) as well as those not previously reported in cancer (miR-376a and miR-301). Most of the top aberrantly expressed miRNAs displayed increased expression in the tumor. Expression of the active, mature microRNA was validated using a real-time PCR assay to quantify the mature microRNA and Northern blotting. Reverse transcription in situ PCR showed that three of the top differentially expressed miRNAs (miR-221, -376a and -301) were localized to tumor cells and not to stroma or normal acini or ducts. Aberrant microRNA expression may offer new clues to pancreatic tumorigenesis and may provide diagnostic biomarkers for pancreatic adenocarcinoma.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":16966691,"Year":2006,"Title":"MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior.","Abstract":"PURPOSE: We investigated the global microRNA expression patterns in normal pancreas, pancreatic endocrine tumors and acinar carcinomas to evaluate their involvement in transformation and malignant progression of these tumor types. MicroRNAs are small noncoding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translation inhibition. Recent evidence indicates that microRNAs can contribute to tumor development and progression and may have diagnostic and prognostic value in several human malignancies. MATERIALS AND METHODS: Using a custom microarray, we studied the global microRNA expression in 12 nontumor pancreas and 44 pancreatic primary tumors, including 12 insulinomas, 28 nonfunctioning endocrine tumors, and four acinar carcinomas. RESULTS: Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis. CONCLUSION: These results suggest that alteration in microRNA expression is related to endocrine and acinar neoplastic transformation and progression of malignancy, and might prove useful in distinguishing tumors with different clinical behavior.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":16461460,"Year":2006,"Title":"A microRNA expression signature of human solid tumors defines cancer gene targets.","Abstract":"Small noncoding microRNAs (miRNAs) can contribute to cancer development and progression and are differentially expressed in normal tissues and cancers. From a large-scale miRnome analysis on 540 samples including lung, breast, stomach, prostate, colon, and pancreatic tumors, we identified a solid cancer miRNA signature composed by a large portion of overexpressed miRNAs. Among these miRNAs are some with well characterized cancer association, such as miR-17-5p, miR-20a, miR-21, miR-92, miR-106a, and miR-155. The predicted targets for the differentially expressed miRNAs are significantly enriched for protein-coding tumor suppressors and oncogenes (P < 0.0001). A number of the predicted targets, including the tumor suppressors RB1 (Retinoblastoma 1) and TGFBR2 (transforming growth factor, beta receptor II) genes were confirmed experimentally. Our results indicate that miRNAs are extensively involved in cancer pathogenesis of solid tumors and support their function as either dominant or recessive cancer genes.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-21"}
{"PMID":30410604,"Year":2018,"Title":"Serum level of co-expressed hub miRNAs as diagnostic and prognostic biomarkers for pancreatic ductal adenocarcinoma.","Abstract":"Background: Sensitive and specific non-invasive biomarkers are urgently needed in order to improve the survival of patients with pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related death. We aim to identify serum hub miRNAs as potential diagnostic and prognostic biomarkers for PDAC. Methods: A total of 2578 serum miRNA expression data from 88 PDAC patients and 19 healthy subjects were downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was constructed and significant modules were extracted from the network by WGCNA R package. Network modules and hub miRNAs closely related to PDAC were identified. The prognostic value of hub miRNAs was assessed by Kaplan-Meier overall survival analysis. Results: Two modules strongly associated with PDAC were identified by WGCNA, which were labeled as turquoise and brown respectively. Within each module, twenty hub miRNAs were found. At the functional level, turquoise module was mainly associated with tumorigenesis pathways such as P53 and WNT signaling pathway, while the brown module was mostly related to the pathways of cancer such as RNA transport and MAPK signaling pathway. Utilizing overall survival analyses, five \"real\" miRNAs were able to stratify PDAC patients into low-risk and high-risk groups. Conclusions: The association of specific Hub miRNAs with the development of pancreatic cancer was established by WGCNA analysis. Five miRNAs (mir-16-2-3p, mir-890, mir-3201, mir-602, and mir-877) were identified as potential diagnostic and prognostic biomarkers for PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-890"}
{"PMID":30988777,"Year":2019,"Title":"MicroRNA-634 functions as a tumor suppressor in pancreatic cancer via directly targeting heat shock-related 70-kDa protein 2.","Abstract":"Pancreatic cancer (PC) is one of the most malignant types of human cancer and has an extremely poor prognosis. MicroRNAs (miRs) reportedly serve a critical role in pancreatic ductal adenocarcinoma (PDAC) progression. Understanding the expression patterns and functions of miRs may provide strategies for the diagnosis and treatment of patients with PC. In particular, miR-634 is attracting interest due to its critical role in regulating the biology of some types of cancer. However, the expression patterns, biological function and molecular mechanism of miR-634 in PC remain unknown. In the present study, miR-634 expression levels in PC tissues and cell lines were significantly downregulated. Notably, the ectopic overexpression of miR-634 in PC cells inhibited tumor progression, whereas miR-634 silencing reversed these effects. Furthermore, reverse transcription-quantitative polymerase chain reaction, western blot analysis and the dual-luciferase assay revealed that miR-634 regulated heat shock-related 70 kDa protein 2 (HSPA2) by directly binding to its 3-untranslated region. In clinical samples of PC, miR-634 was inversely correlated with HSPA2, which was upregulated in PC. In the rescue experiment, HSPA2 overexpression partially abrogated the effects of miR-634 mimicry on biological function. In conclusion, miR-634 functioned as a tumor suppressor in regulating PC progression by targeting HSPA2 and may therefore be a novel potential therapeutic target for PC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-634"}
{"PMID":21913185,"Year":2012,"Title":"Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer.","Abstract":"This study was performed to identify plasma microRNAs (miRNAs) as diagnostic biomarkers for pancreatic cancer (PCa) and to assess their supplementary role with serum CA19-9 in early identification of tumors. Plasma RNAs were extracted from 140 PCa patients, 111 chronic pancreatitis (CP) patients and 68 normal controls, and the relative abundances of seven miRNAs (miR-16, 21, 155, 181a, 181b, 196a and 210) were measured using real-time PCR. Their diagnostic utility for PCa and correlation with clinical characteristics were analyzed. All seven miRNAs were significantly aberrantly upregulated in the PCa group compared with both the CP and normal groups, between which only four miRNAs (miR-155, 181a, 181b and 196a) were significantly different. Logistic modeling proved that only miR-16 and miR-196a possessed an independent role in discriminating PCa from normal and CP. Furthermore, after including serum CA19-9 in the logistic model, the combination of miR-16, miR-196a and CA19-9 was more effective for discriminating PCa from non-PCa (normal+CP) (AUC-ROC, 0.979; sensitivity, 92.0%; specificity, 95.6%), and for discriminating PCa from CP (AUC-ROC, 0.956; sensitivity, 88.4%; specificity, 96.3%) compared with the miRNA panel (miR-16+miR-196a) or CA19-9 alone. Most significantly, the combination was effective at identification of tumors in Stage 1 (85.2%). In conclusion, plasma miRNAs were effective for distinguishing PCa from non-PCa (normal+CP). The combination of miR-16, miR-196a and CA19-9 was more effective for PCa diagnosis, especially in early tumor screening.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-155"}
{"PMID":30419348,"Year":2019,"Title":"Exosomes derived from human umbilical cord mesenchymal stromal cells deliver exogenous miR-145-5p to inhibit pancreatic ductal adenocarcinoma progression.","Abstract":"The roles of miRNAs in the development of cancer have made them promising tools for novel therapeutic approaches. However, the successful delivery of miRNAs to cancer cells has been hampered by difficulties in developing an effective and sustainable delivery mechanism. Exosomes are small endogenous membrane vesicles that mediate communication between cells by delivering genetic materials. Thus, given their intrinsic properties, exosomes have been a focus for use as biological delivery vehicles for miRNAs transfer. Whether exosomes can effectively deliver exogenous miRNAs to pancreatic ductal adenocarcinoma (PDAC) cells has not been thoroughly investigated. Here, we used exosomes from human umbilical cord mesenchymal stromal cells (hucMSCs) to deliver exogenous miR-145-5p, which inhibited PDAC cell proliferation and invasion and increased apoptosis and cell cycle arrest, concomitant with decreased Smad3 expression in vitro. Using a mouse model, we also demonstrated that overexpressing miR-145-5p significantly reduced the growth of xenograft tumors in vivo. Our findings provide novel insights that exosomes might be an attractive therapeutic vehicle for the clinical administration of miRNAs in patients with PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-145"}
{"PMID":28657147,"Year":2018,"Title":"LncRNA-PVT1 promotes pancreatic cancer cells proliferation and migration through acting as a molecular sponge to regulate miR-448.","Abstract":"The identification and characterization of long non-coding RNAs (lncRNAs) in diverse biological process has currently developed rapidly. LncRNA-PVT1, located adjacent to the MYC locus on chromosomal region 8q24, has been reported to be associated with many biological processes. However, the function and mechanism of PVT1 in pancreatic carcinoma (PC) is poorly understood. In this present study, we first measured the level of PVT1 in the PC cell lines and tissues by quantitative real-time PCR (qRT-PCR), and then employed loss-of-function and gain-of-function approaches to explore the association between PVT1 expression levels and PC cell proliferation/migration ability. Furthermore, bioinformatics analysis was utilized to show that PVT1 contains binding site for miR-448 and an inverse correlation between PVT1 and miR-448 was obtained in PC specimens. Additionally, dual luciferase reporter assay, RNA-binding protein immunoprecipitation (RIP) and applied biotin-avidin pulldown system were applied to further confirm that PVT1 directly bind with microRNA binding site harboring in the PVT1 sequence. Then, SERBP1 was identified as a target of miR-448 according to the gene expression array analysis of PC clinical samples. Together, we revealed that PVT1 functions as an endogenous \"sponge\" by competing for miR-448 binding to regulate the miRNA target SERBP1 and, therefore, promotes the proliferation and migration of PC cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-448"}
{"PMID":25084000,"Year":2015,"Title":"Interaction of Serum microRNAs and Serum Folate With the Susceptibility to Pancreatic Cancer.","Abstract":"OBJECTIVES: The aim of this study was to investigate whether 6 candidate serum miRNAs and their interactions with serum folate level were associated with the risk for pancreatic cancer (PC). METHOD: A hospital-based case-control study including 74 incident PC cases and 74 controls was conducted. Serum folate and miRNAs were determined by radioimmunoassay and real-time quantitative polymerase chain reaction, respectively. Cell lines AsPC-1 and PANC-1 were used for in vitro study. RESULTS: MiR-16 was elevated (P = 0.030-0.043) and miR-103 was reduced (P = 0.018-0.020) in PC after adjustment for age, sex, and smoking; however, after additional adjustment for folate, only miR-103 was significantly different between cases and controls (P = 0.010). After converting the relative expression of miRNAs into binary variables and adjusting for age, sex, smoking, and folate, the subjects with low miR-103 or low miR-601 were observed to have a higher risk for PC, with odds ratios of 2.33 (95% confidence interval, 1.06-5.10) and 2.37 (95% confidence interval, 1.07-5.26), respectively. Multifactor dimensionality reduction analysis showed a significant interaction for miR-16, folate, and smoking (cross-validation consistency, 10/10; mean testing accuracy, 0.696; P = 0.013). Interaction between miR-16 and folate was also verified in the AsPC-1 cells. CONCLUSION: Serum miR-103; miR-601; and interactions among serum miR-16, folate, and smoking are associated with PC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-601"}
{"PMID":30021866,"Year":2019,"Title":"Evaluating gastroenteropancreatic neuroendocrine tumors through microRNA sequencing.","Abstract":"Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be challenging to evaluate histologically. MicroRNAs (miRNAs) are small RNA molecules that often are excellent biomarkers due to their abundance, cell-type and disease stage specificity and stability. To evaluate miRNAs as adjunct tissue markers for classifying and grading well-differentiated GEP-NETs, we generated and compared miRNA expression profiles from four pathological types of GEP-NETs. Using quantitative barcoded small RNA sequencing and state-of-the-art sequence annotation, we generated comprehensive miRNA expression profiles from archived pancreatic, ileal, appendiceal and rectal NETs. Following data preprocessing, we randomly assigned sample profiles to discovery (80%) and validation (20%) sets prior to data mining using machine-learning techniques. High expression analyses indicated that miR-375 was the most abundant individual miRNA and miRNA cistron in all samples. Leveraging prior knowledge that GEP-NET behavior is influenced by embryonic derivation, we developed a dual-layer hierarchical classifier for differentiating GEP-NET types. In the first layer, our classifier discriminated midgut (ileum, appendix) from non-midgut (rectum, pancreas) NETs based on miR-615 and -92b expression. In the second layer, our classifier discriminated ileal from appendiceal NETs based on miR-125b, -192 and -149 expression, and rectal from pancreatic NETs based on miR-429 and -487b expression. Our classifier achieved overall accuracies of 98.5% and 94.4% in discovery and validation sets, respectively. We also found provisional evidence that low- and intermediate-grade pancreatic NETs can be discriminated based on miR-328 expression. GEP-NETs can be reliably classified and potentially graded using a limited panel of miRNA markers, complementing morphological and immunohistochemistry-based approaches to histologic evaluation.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-487"}
{"PMID":26261532,"Year":2015,"Title":"MicroRNA-200c overexpression inhibits chemoresistance, invasion and colony formation of human pancreatic cancer stem cells.","Abstract":"INTRODUCTION: Cancer stem cells (CSCs) are believed to be 'seed cell' in cancer recurrence and metastasis. MicroRNAs (miRNAs) have emerged as potential therapeutic candidates due to their ability to regulate multiple targets involved in tumor progression and chemoresistance. The goal of this study was to investigate the role of miRNA-200c (miR-200c) in regulating colony formation, invasion and chemoresistance of human pancreatic cancer stem cells (PCSCs). METHODS: PCSCs with CD24(+)CD44(+)ESA(+) as the marker was sorted from PANC-1 cell line by fluorescence activated cell sorter (FACS). Quantitative real-time PCR (qRT-PCR) assay was used to detect the expression of miR-200c in PCSCs and PANC-1 cells. Transfection of miR-200c mimic into PCSCs was performed to establish miR-200c over-expressed cells. The effects of overexpressing miR-200c on PCSCs were examined by cell colony forming, invasion and survival assays in vitro. RESULTS: Our data showed that CD24(+)CD44(+)ESA(+) PCSCs (0.5%) were isolated from PANC-1 cells. Expression of miR-200c was significantly reduced in PCSCs compared with PANC-1 cells. In addition, the capability of colony formation, invasion and chemoresistance were markedly increased in PCSCs than that in PANC-1 cells. Adverse results were obtained in miR-200c overexpressing PCSCs transfected with miR-200c mimic. CONCLUSION: Our study demonstrated that miR-200c overexpression could decrease colony formation, invasion and chemoresistance of PCSCs. It may become a new therapeutic target for gene therapy in patients suffered from pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-200"}
{"PMID":27631726,"Year":2017,"Title":"Plasma miR-22-3p, miR-642b-3p and miR-885-5p as diagnostic biomarkers for pancreatic cancer.","Abstract":"BACKGROUND: Diagnosis of pancreatic cancer (PC) by using sensitive and specific biomarkers is considered necessary. MiRNAs are master regulators of gene expression and several biological processes, and they are dysregulated in various cancers, where they play a vital role in either cancer progression or suppression. So, this study was designed to investigate the role of plasma miR-22-3p, miR-642b-3p and miR-885-5p expression as possible diagnostic markers in PC patients as compared to serum CA19-9. In addition, the correlation of those miRNAs and CA19-9 with clinical characteristics of PC patients was analyzed. METHODS: The expression levels of selected miRNAs and serum CA19-9 concentration were determined for 35 patients with PDAC and 15 healthy controls by quantitative real-time RT-PCR and electro-chemiluminescence immune assay, respectively. The sensitivities of miRNAs as biomarkers of PC were evaluated and compared with CA19-9 using a receiver operating characteristic analysis. RESULTS: The levels of three miRNAs (miR-22-3p, miR-642b-3p and miR-885-5p) and CA19-9 were significantly higher in PC patients, even those with early-stage disease (IB and IIB), than in healthy control. Both miRNAs and CA19-9 were associated with tumor stage. The high sensitivities of the three selected miRNAs and CA19-9 were observed. CONCLUSION: The measurement of miR-22-3p, miR-642b-3p and miR-885-5p may prove to have clinical utility in diagnosis of PC. Those miRNAs are ideal early biomarkers for PC diagnosis. So, they can effectively be used with serum CA19-9 for PC screening in early tumor stage.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-885"}
{"PMID":28720759,"Year":2017,"Title":"Depleted tumor suppressor miR-107 in plasma relates to tumor progression and is a novel therapeutic target in pancreatic cancer.","Abstract":"This study explored decreased tumor suppressor microRNA (miRNA) plasma levels in pancreatic cancer (PCa) patients to clarify their potential as novel biomarkers and therapeutic targets. We used the microRNA array-based approach to select candidates by comparing plasma levels between PCa patients and healthy volunteers. Six down-regulated miRNAs (miR-107, miR-126, miR-451, miR-145, miR-491-5p, and miR-146b-5p) were selected. Small- and large-scale analyses using samples from 100 PCa patients and 80 healthy volunteers revealed that miR-107 was the most down-regulated miRNA in PCa patients compared with healthy volunteers (P < 0.0001; area under the receiver-operating characteristic curve, 0.851). A low miR-107 plasma level was significantly associated with advanced T stage, N stage, and liver metastasis and was an independent factor predicting poor prognosis in PCa patients (P = 0.0424; hazard ratio, 2.95). miR-107 overexpression in PCa cells induced G1/S arrest with the production of p21 and inhibited cell proliferation through the transcriptional regulation of Notch2. In vivo, the restoration and maintenance of the miR-107 plasma level significantly inhibited tumor progression in mice. Depletion of the tumor suppressor miR-107 in plasma relates to tumor progression and poor outcomes. The restoration of the plasma miR-107 level might be a novel anticancer treatment strategy for PCa.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-107"}
{"PMID":25807437,"Year":2015,"Title":"Identification of miRNA-mRNA crosstalk in pancreatic cancer by integrating transcriptome analysis.","Abstract":"OBJECTIVE: Pancreatic cancer is one of the most lethal diseases, and the pathogenesis remains largely unknown. To this end, we performed an integrated analysis of miRNA and mRNA expression data to explore the deregulation of miRNA and mRNA and regulatory processes underlying pancreatic cancer. MATERIALS AND METHODS: We combined mRNA and miRNA expression data with miRNA target predictions to infer new miRNA regulation activities in pancreatic cancer. We first integrated miRNA and mRNA expression profiling separately to identify differently expressed miRNA and mRNA in pancreatic cancer. Then we adopted miRWalk databases prediction to obtain potential target genes of differently expressed miRNA, and compared these target genes to the gene list of integrated mRNA expression profiling to select differentially expressed miRNA-target gene whose expression was reversely correlated with that of corresponding miRNAs. Gene Ontology (GO) classification analyses and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were employed to understand the functions and pathways of miRNA target genes. Finally we construct a miRNA-target gene regulatory network. RESULTS: 42 differentially expressed miRNAs, 1376 differentially expressed mRNAs were identified by combining three expression profiles of miRNA and mRNA separately in pancreatic cancer, 146 miRNA target genes were found in the gene list of integrated mRNA expression profiling based on bioinformatics prediction. Functional annotation was performed to understand the functions and pathways of miRNA target genes. Finally, we constructed a miRNA-target gene regulatory network including 206 miRNA-target gene pairs. Five miRNAs (hsa-miR-130b, hsa-miR-106b, hsa-miR-181c, hsa-miR-153 and hsa-miR-125a-5p) demonstrated the highest connectivities, whereas three miRNAs (MYC, E2F1 and IL6) were the mRNAs with the highest connectivities. CONCLUSIONS: Our findings may provide new insights into the knowledge of molecular mechanisms of pancreatic cancer and development of novel targeting therapies.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-153"}
{"PMID":27666488,"Year":2016,"Title":"MicroRNAs modulate the expression of the SOX18 transcript in lung squamous cell carcinoma.","Abstract":"Recent statistics show that lung cancer is the second most common malignant tumor in the world (14% of all cancers in the USA), both in terms of morbidity and mortality. The mortality of this type of tumor shows an increasing trend (28% for men and 26% for women). Lung squamous cell carcinoma (LSCC) is the secondlargest histological subtype of nonsmall cell lung cancers (NSCLCs) after adenocarcinoma. SRYrelated HMGbox 18 (SOX18) protein is an important transcription factor involved in the development of the cardiovascular system and the lymphatic ducts. In addition, it was observed that SOX18 functions in wound healing processes and the development of atherosclerosis. Likewise, an increased level of this protein was found in melanomas and malignant pancreatic, stomach and breast tumors. Furthermore, high expression of SOX18 in gastric cancer stromal cells was found to be associated with a poor patient prognosis. In the present study, we analyzed the expression of the SOX18 protein and the mRNA level in postoperative samples of LSCC and nonmalignant lung tissues (NMLTs), and a disparity in both levels was observed. Because of the fact that microRNAs (miRNAs) play important roles in the initiation and progression of lung cancer, the main aim of this study was to identify the miRNAs that interact with the SOX18 transcript in NSCLC cases. SOX18 mRNA expression level was significantly lower in the LSCC tissues than that noted in the NMLTs (p<0.01). However, protein levels were higher in the LSCC cases compared to these levels in the NMLTs (p<0.0001). We showed that miR7a and miR243p were expressed more highly in the NMLTs than levels in the LSCC samples, and that they could be switched off in lung cancer tissue. Additionally, correlations between RQvalues of SOX18 in NMLTs and LSCC samples (r=0.43, p=0.019), and between miR7a and miR243p in NMLT cases (r=0.4, p=0.057) as well as in the LSCC samples (r=0.51, p=0.012) were noted. In conclusion, miRNAs interact with the mRNA of the SOX18 gene, but the mechanism by which they could be inhibited in cancer cells requires further examination.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-24"}
{"PMID":29976637,"Year":2018,"Title":"Pre-operative Plasma miR-21-5p Is a Sensitive Biomarker and Independent Prognostic Factor in Patients with Pancreatic Ductal Adenocarcinoma Undergoing Surgical Resection.","Abstract":"Blood plasma microRNAs (miRNAs) are emerging as a clinically useful tool for non-invasive detection and prognosis estimation in various cancer types including pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to provide an independent validation of circulating miRNAs identified in previous studies as diagnostic and/or prognostic biomarkers in PDAC. Based on the literature search, 6 miRNAs were chosen as candidates for independent validation; miR-21-5p, miR-375, miR-155, miR-17-5p, miR-126-5p and miR-1290. Validation of these miRNAs was performed in a cohort of 25 patients with PDAC undergoing surgical resection and 24 healthy donors. Plasma levels of miRNAs were determined using quantitative real-time PCR. We confirmed significantly higher levels of all tested miRNA in blood plasma of PDAC patients in comparison to healthy controls with miR-21-5p showing the highest analytical performance (p<0.001; AUC>0.99). Increased levels of miR-21-5p (p=0.045) and miR-375 (p=0.013) were significantly associated with overall survival. Multivariate analysis demonstrated that miR-21-5p is a significant unfavorable prognostic factor independent on other clinical variables including adjuvant chemotherapy (hazard ratio 2.95; 95% CI 1.06-8.18; p=0.038). Our preliminary data indicate promising diagnostic and prognostic utility of plasma miR-21-5p in PDAC patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-17"}
{"PMID":31311829,"Year":2019,"Title":"Identification of novel genes associated with a poor prognosis in pancreatic ductal adenocarcinoma via a bioinformatics analysis.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a class of the commonest malignant carcinomas. The present study aimed to elucidate the potential biomarker and prognostic targets in PDAC. The array data of GSE41368, GSE43795, GSE55643, and GSE41369 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) and differentially expressed microRNAs (DEmiRNAs) in PDAC were obtained by using GEO2R, and overlapped DEGs were acquired with Venn Diagrams. Functional enrichment analysis of overlapped DEGs and DEmiRNAs was conducted with Metascape and FunRich, respectively. The protein-protein interaction (PPI) network of overlapped DEGs was constructed by STRING and visualized with Cytoscape. Overall survival (OS) of DEmiRNAs and hub genes were investigated by Kaplan-Meier (KM) plotter (KM plotter). Transcriptional data and correlation analyses among hub genes were verified through GEPIA and Human Protein Atlas (HPA). Additionally, miRNA targets were searched using miRTarBase, then miRNA-DEG regulatory network was visualized with Cytoscape. A total of 32 DEmiRNAs and 150 overlapped DEGs were identified, and Metascape showed that DEGs were significantly enriched in cellular chemical homeostasis and pathways in cancer, while DEmiRNAs were mainly enriched in signal transduction and Glypican pathway. Moreover, seven hub genes with a high degree, namely, V-myc avian myelocytomatosis viral oncogene homolog (MYC), solute carrier family 2 member 1 (SLC2A1), PKM, plasminogen activator, urokinase (PLAU), peroxisome proliferator activated receptor gamma (PPARG), MET proto-oncogene, receptor tyrosine kinase (MET), and integrin subunit alpha 3 (ITGA3), were identified and found to be up-regulated between PDAC and normal tissues. miR-135b, miR-221, miR-21, miR-27a, miR-199b-5p, miR-143, miR-196a, miR-655, miR-455-3p, miR-744 and hub genes predicted poor OS of PDAC. An integrative bioinformatics analysis identified several hub genes that may serve as potential biomarkers or targets for early diagnosis and precision target treatment of PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-143"}
{"PMID":26063036,"Year":2015,"Title":"miR-215 overexpression distinguishes ampullary carcinomas from pancreatic carcinomas.","Abstract":"Distinguishing ampullary carcinoma from pancreatic carcinoma is important because of their different prognoses. microRNAs are differentially expressed according to the tissue of origin. However, there is rare research on the differential diagnosis between the two types of cancers by microRNA in periampullary cancers. The present study was undertaken to compare microRNA profiles between ampullary and pancreatic carcinomas using microarrays. miR-215 was most significantly overexpressed in ampullary carcinomas; whereas the expressions of miR-134 and miR-214 were significantly lower in ampullary carcinomas than in pancreatic carcinomas. When these discriminatory microRNAs were applied to liver metastases, they were correctly predicted for the tissue of origin. Although this study is limited by small sample size, striking difference in microRNA expression and concordant expression of discriminating microRNAs in primary tumors and metastases suggest that these novel discriminatory microRNAs warrant future validation.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-134"}
{"PMID":23638815,"Year":2013,"Title":"Distinct miRNA profiles are associated with malignant transformation of pancreatic cystic tumors revealing potential biomarkers for clinical use.","Abstract":"Pancreatic cysts are now being detected more frequently owing to increased recognition and the liberal use of cross-sectional imaging. There is a spectrum of pancreatic cystic lesions ranging from the completely benign inflammatory to the highly malignant. Pancreatic cystic tumors, especially those with a mucinous epithelial lining such as the intraductal papillary mucinous neoplasms (IPMNs), have the potential to become malignant. The evaluated paper provides further evidence for miRNAs as diagnostic biomarkers for detecting dysplastic and malignant change in IPMNs, which may be useful for future clinical decision making. IPMNs of varying degrees of dysplasia, as well as IPMN with carcinoma, pancreatic ductal adenocarcinoma and normal pancreas samples were examined by microarray. Upregulation of miR-21, miR-155 and miR-708 was found to occur during IPMN malignant transformation. Here, the authors evaluate the published miRNA profiles of premalignant pancreatic lesions in order to consolidate these data.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-155"}
{"PMID":28383557,"Year":2017,"Title":"Silencing NKG2D ligand-targeting miRNAs enhances natural killer cell-mediated cytotoxicity in breast cancer.","Abstract":"NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DLs). NKG2DLs are expressed on malignant cells and sensitize them to early elimination by cytotoxic lymphocytes. We investigated the clinical importance of NKG2DLs and the mechanism of NKG2DL regulation in breast cancer (BC). Among the NKG2DLs MICA/B and ULBP1/2/3, the expression levels of MICA/B in BC tissues were inversely associated with the Tumor Node Metastasis stage. We first found that the high expression of MICB, but not MICA, was an independent prognostic factor for overall survival in patients with BC. Investigation into the mechanism revealed that a group of microRNAs (miRNAs) belonging to the miR-17-92 cluster, especially miR-20a, decreased the expression of ULBP2 and MICA/B. These miRNAs downregulated the expression of MICA/B by targeting the MICA/B 3'-untranslated region and downregulated ULBP2 by inhibiting the MAPK/ERK signaling pathway. Functional analysis showed that the silencing of NKG2DL-targeting miRNAs in BC cells increased NK cell-mediated cytotoxicity in vitro and inhibited immune escape in vivo. In addition, histone deacetylase inhibitors (HDACis) increased NKG2DL expression in BC cells by inhibiting members of the miR-17-92 cluster. Thus, targeting miRNAs with antisense inhibitors or HDACis may represent a novel approach for increasing the immunogenicity of BC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-20"}
{"PMID":25887381,"Year":2015,"Title":"The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells.","Abstract":"OBJECTIVE: Cancer stem cells (CSCs) represent the root of many solid cancers including pancreatic ductal adenocarcinoma, are highly chemoresistant and represent the cellular source for disease relapse. However the mechanisms involved in these processes still need to be fully elucidated. Understanding the mechanisms implicated in chemoresistance and metastasis of pancreatic cancer is critical to improving patient outcomes. DESIGN: Micro-RNA (miRNA) expression analyses were performed to identify functionally defining epigenetic signatures in pancreatic CSC-enriched sphere-derived cells and gemcitabine-resistant pancreatic CSCs. RESULTS: We found the miR-17-92 cluster to be downregulated in chemoresistant CSCs versus non-CSCs and demonstrate its crucial relevance for CSC biology. In particular, overexpression of miR-17-92 reduced CSC self-renewal capacity, in vivo tumourigenicity and chemoresistance by targeting multiple NODAL/ACTIVIN/TGF-beta1 signalling cascade members as well as directly inhibiting the downstream targets p21, p57 and TBX3. Overexpression of miR-17-92 translated into increased CSC proliferation and their eventual exhaustion via downregulation of p21 and p57. Finally, the translational impact of our findings could be confirmed in preclinical models for pancreatic cancer. CONCLUSIONS: Our findings therefore identify the miR-17-92 cluster as a functionally determining family of miRNAs in CSCs, and highlight the putative potential of developing modulators of this cluster to overcome drug resistance in pancreatic CSCs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-17"}
{"PMID":25220761,"Year":2014,"Title":"MicroRNA-216a inhibits pancreatic cancer by directly targeting Janus kinase 2.","Abstract":"MicroRNA (miR)-216a expression is significantly downregulated in human pancreatic cancer, however, the underlying mechanism remains unknown. In the present study, we aimed to identify and characterize the direct target gene and potential function of miR-216a in pancreatic cancer cells. Bioinformatics analysis and dual-luciferase reporter gene assay showed that Janus kinase 2 (JAK2) was a direct target gene of miR-216a. Quantitative polymerase chain reaction and western blot analysis demonstrated that miR-216a decreased the mRNA and protein levels of JAK2 in pancreatic cancer cells. Phosphorylation of the signal transducer and activator of transcription 3 (STAT3) was also downregulated by miR-216a, whereas the anti-miR-216a treatment had an opposite effect. Treatment of pancreatic cancer cells with miR-216a significantly inhibited cell growth and promoted cell apoptosis. In addition, the downstream genes of JAK2/STAT3, survivin and X-linked inhibitor of apoptosis protein, which are antiapoptotic genes, were also decreased by miR-216a. Moreover, miR-216a overexpression markedly inhibited the JAK2/STAT3 signaling pathway and xenograft tumor growth in vivo. Compared with miR-216a treatment, anti-miR-216a treatment exhibited opposite effects throughout the entire experiment, confirming the inhibitory effect of miR-216a on pancreatic cancer by regulating the JAK2/STAT3 signaling pathway. The results provided evidence that miR-216a targeting JAK2 negatively regulated the development of pancreatic cancer cells and may be used to develop a miRNA-based therapeutic strategy against pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-216"}
{"PMID":22311263,"Year":2012,"Title":"Aberrant elevated microRNA-146a in dendritic cells (DC) induced by human pancreatic cancer cell line BxPC-3-conditioned medium inhibits DC maturation and activation.","Abstract":"It has been shown that the function of dendritic cell (DC) is suppressed in pancreatic cancer patients; however, the detailed mechanism involved in it remains unclear. Here, we used medium conditioned by a highly metastatic human pancreatic cancer cell line BxPC-3 [BxPC-3-conditioned medium (BxCM)] to culture human CD14+ monocyte-derived DCs in vitro. Both DC differentiation and antigen presentation function were inhibited by BxCM. The microRNA-146a (miRNA-146a) expression is aberrantly up-regulated in BxCM-treated DCs. In addition, inhibition of aberrant miRNA-146a expression partly rescues the BxCM-induced defects in differentiation and function of DCs, which may be through regulation of Smad4 expression. Taken together, our findings indicate that aberrant miRNA-146a expression is one of main factors responsible for inhibition of DC maturation and antigen presentation function, and this inhibitory effect on DCs may be due to the repression of Smad4 mediated signal pathway by BxCM.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-146"}
{"PMID":29218103,"Year":2017,"Title":"MicroRNA-429 sensitizes pancreatic cancer cells to gemcitabine through regulation of PDCD4.","Abstract":"One of the features for pancreatic cancer is that it is often resistant to chemotherapy treatment, which is one of the major hindrances in the treatment of this malignancy. Previous studies indicated that the microRNAs (miRNAs) could mediate resistance of tumor cells to chemotherapy drug in the cancer progression. In the present study, we are aimed to examine whether microRNA-429 was involved in mediating the chemo-resistance of pancreatic cancer cells to gemcitabine. Firstly, a gemcitabine-resistant pancreatic cancer cell line (SW1990/GZ) derived from cell line (SW1990) was constructed and found to possess a decreased expression of miR-429 when it is compared to the original cell line. Ectopic expression of miR-429 in SW1990/GZ increased the cellular sensibility to the treatment of gemcitabine, which is coincided with increased expression of PDCD4. As a tumor suppressor, we found that PDCD4 knockdown in SW1990/GZ cells increased its own chemo-resistance to GZ, which indicates PDCD4 also play a regulative role on the GZ-resistance in the pancreatic cancer. To further confirm the function of miR-429 and PDCD4 in gemcitabine-resistant pancreatic cancer, a xenograft nude mouse model was utilized to examine whether miR-429 can restore treatment response of gemcitabine in gemcitabine-resistant xenografts, while protein levels of PDCD4 were up-regulated. Together with those results, these findings collectively provided that miR-429 could enhancer GZ sensitivity via regulation of PDCD4 expression in pancreatic cancer cells, which may offer a novel therapeutic target for the chemotherapy resistance in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-429"}
{"PMID":22531314,"Year":2012,"Title":"miR-409-3p inhibits HT1080 cell proliferation, vascularization and metastasis by targeting angiogenin.","Abstract":"Although the expression of angiogenin (ANG), an angiogenic and tumorigenic factor, is elevated in various types of cancers, its regulation mechanism remains unclear. In the present study, in silico search predicted that miR-409-3p targeted to the 3' untranslated region (3'UTR) of the ANG mRNA. Overexpression of miR-409-3p in fibrosarcoma HT1080 cells resulted in decreased steady-state level of ANG transcript and ANG production which were achieved through direct binding of this miRNA to the ANG 3'UTR. The suppressions of miR-409-3p to rRNA transcription, cell proliferation and vasculogenic mimicry could be partially restored by overexpression of ANG with a mutated binding site of miR-409-3p within the ANG 3'UTR. Ectopic expression of miR-409-3p in transplanted HT1080 cells led to the retardation of tumor growth, vascularization and lung metastasis in mouse tumor xenografts. In these xenografts tissues, the expression of miR-409-3p displayed an inverse correlation with ANG, which was also detected in human fibrosarcoma samples. In addition, the suppression effects of miR-409-3p on cell proliferation and angiogenesis in vitro were also found in human umbilical vein endothelial cells. Taken together, these data demonstrate that miR-409-3p inhibits tumor growth, vascularization and metastasis through down-regulating ANG expression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-409"}
{"PMID":27267055,"Year":2016,"Title":"Serum microRNA-196 and microRNA-200 in pancreatic ductal adenocarcinoma of patients with diabetes mellitus.","Abstract":"BACKGROUND/OBJECTIVES: Our aim was to compare expressions of 6 microRNAs (miRNAs) in patients with pancreatic ductal adenocarcinoma (PAC) and non-cancer patients, moreover according to the presence or absence of diabetes mellitus. METHODS: Expressions of miRNA-192, -196, -200, -21, -30 and -423 were measured in 77 patients with PAC and 64 non-cancer patients (34 patients with type 2 DM and 30 control persons). 60 patients with PAC (78%) had DM or prediabetes and it was of new-onset (less than 2 years before the cancer diagnosis) in 44 out of them. RESULTS: The expressions of all microRNAs were 1.4-3.7 times higher (significantly) in the PAC group compared to non-cancer patients. No difference was found between PAC diabetic and PAC non-diabetic patients. MicroRNA-200 was significantly higher in PAC patients with significant body weight loss against those without weight loss. Adding miRNA-196 and -200 to the current marker CA 19-9 improved the discriminative ability of the test (compared to CA 19-9 alone). CONCLUSION: MicroRNA-196 and -200 could be used as additional markers in PAC diagnosis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-200"}
{"PMID":28542740,"Year":2017,"Title":"Plasma microRNAs as biomarkers of pancreatic cancer risk in a prospective cohort study.","Abstract":"Noninvasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case-control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate prediagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR-10a, -10b, -21-3p, -21-5p, -30c, -106b, -155 and -212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status and age/date/time of blood collection. MiR levels in prediagnostic plasma samples were determined by quantitative RT-PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR-10b, -21-5p, -30c and -106b levels were significantly higher in cases diagnosed within 2 years of blood collection compared to matched controls (all p-values <0.04). Based on adjusted logistic regression models, levels for six miRs (miR-10a, -10b, -21-5p, -30c, -155 and -212) overall, and for four miRs (-10a, -10b, -21-5p and -30c) at shorter follow-up time between blood collection and diagnosis (<\/=5 yr, <\/=2 yr), were statistically significantly associated with risk. A score based on the panel showed a linear dose-response trend with risk (p-value = 0.0006). For shorter follow-up (<\/=5 yr), AUC for the score was 0.73, and for individual miRs ranged from 0.73 (miR-212) to 0.79 (miR-21-5p).","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-212"}
{"PMID":27765914,"Year":2016,"Title":"MiRNA-145 increases therapeutic sensibility to gemcitabine treatment of pancreatic adenocarcinoma cells.","Abstract":"Pancreatic adenocarcinoma is one of the most leading causes of cancer-related deaths worldwide. Although recent advances provide various treatment options, pancreatic adenocarcinoma has poor prognosis due to its late diagnosis and ineffective therapeutic multimodality. Gemcitabine is the effective first-line drug in pancreatic adenocarcinoma treatment. However, gemcitabine chemoresistance of pancreatic adenocarcinoma cells has been a major obstacle for limiting its treatment effect. Our study found that p70S6K1 plays an important role in gemcitabine chemoresistence. MiR-145 is a tumor suppressor which directly targets p70S6K1 for inhibiting its expression in pancreatic adenocarcinoma, providing new therapeutic scheme. Our findings revealed a new mechanism underlying gemcitabine chemoresistance in pancreatic adenocarcinoma cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-145"}
{"PMID":26644397,"Year":2016,"Title":"Molecular subtypes of pancreatic cancer based on miRNA expression profiles have independent prognostic value.","Abstract":"BACKGROUND AND AIM: Altered microRNAs (miRNA) expression, a typical feature of many cancers, is reportedly associated with prognosis according to several studies. Although numerous studies on miRNAs in pancreatic ductal adenocarcinoma have also attempted to identify prognostic biomarkers, more large-scale clinical studies are needed to establish the clinical significance of the results. Present study aimed to identify prognosis-related molecular subtypes of primary pancreas tumors using miRNA expression profiling. METHODS: Expression profiles of 1733 miRNAs were obtained by using microarray analysis of 104 pancreatic tumors of Korean patients. To detect subgroups informative in predicting the patient's prognosis, we applied unsupervised clustering methods and then analyzed the association of the molecular subgroups with survival time. Then, we constructed a classifier to predict the subgroup using penalized regression models. RESULTS: We have determined three pancreatic ductal adenocarcinoma tumor subtypes associated with prognosis based on miRNA expression profiles. These subtypes showed significantly different survival time for patients with the same clinical conditions. This demonstrates that our prognostic molecular subgroup has independent prognostic utility. The molecular subtypes can be predicted with a classifier of 19 miRNAs. Of the 19 signature miRNAs, miR-106b-star, miR-324-3p, and miR-615 were related to a p53 canonical pathway, and miR-324, miR-145-5p, miR-26b-5p, and miR-574-3p were related to a Cox-2 centered pathway. CONCLUSIONS: Our prognostic molecular subtypes demonstrated that miRNA profiles could be used as prognostic markers. Additionally, we have constructed a classifier that may be used to determine the molecular subgroup of new patient sample data. Further studies are needed for validation.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-145"}
{"PMID":21622730,"Year":2011,"Title":"Restitution of tumor suppressor microRNAs using a systemic nanovector inhibits pancreatic cancer growth in mice.","Abstract":"Mis-expression of microRNAs (miRNA) is widespread in human cancers, including in pancreatic cancer. Aberrations of miRNA include overexpression of oncogenic miRs (Onco-miRs) or downregulation of so-called tumor suppressor TSG-miRs. Restitution of TSG-miRs in cancer cells through systemic delivery is a promising avenue for pancreatic cancer therapy. We have synthesized a lipid-based nanoparticle for systemic delivery of miRNA expression vectors to cancer cells (nanovector). The plasmid DNA-complexed nanovector is approximately 100 nm in diameter and shows no apparent histopathologic or biochemical evidence of toxicity upon intravenous injection. Two miRNA candidates known to be downregulated in the majority of pancreatic cancers were selected for nanovector delivery: miR-34a, which is a component of the p53 transcriptional network and regulates cancer stem cell survival, and the miR-143/145 cluster, which together repress the expression of KRAS2 and its downstream effector Ras-responsive element binding protein-1 (RREB1). Systemic intravenous delivery with either miR-34a or miR-143/145 nanovectors inhibited the growth of MiaPaCa-2 subcutaneous xenografts (P < 0.01 for miR-34a; P < 0.05 for miR-143/145); the effects were even more pronounced in the orthotopic (intrapancreatic) setting (P < 0.0005 for either nanovector) when compared with vehicle or mock nanovector delivering an empty plasmid. Tumor growth inhibition was accompanied by increased apoptosis and decreased proliferation. The miRNA restitution was confirmed in treated xenografts by significant upregulation of the corresponding miRNA and significant decreases in specific miRNA targets (SIRT1, CD44 and aldehyde dehydrogenase for miR34a, and KRAS2 and RREB1 for miR-143/145). The nanovector is a platform with potential broad applicability in systemic miRNA delivery to cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-34"}
{"PMID":30026054,"Year":2018,"Title":"Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment.","Abstract":"Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-199"}
{"PMID":26156803,"Year":2015,"Title":"MicroRNA-133a functions as a tumor suppressor by targeting IGF-1R in hepatocellular carcinoma.","Abstract":"MicroRNAs (miRNAs) are a class of small non-coding RNAs and have critical roles in tumorigenesis and metastasis. A growing body of evidence showed that microRNA-133a (miR-133a) was downregulated and played tumor suppressor roles in gastric, colorectal, bladder, and lung cancer. However, the role and underlying molecular mechanism of miR-133a in hepatocellular carcinoma (HCC) remain unclear. In this study, we analyzed the expression of miR-133a in HCC tissues and HCC cell lines. We find that miR-133a was downregulated in HCC tissues and cell lines and that miR-133a expression negatively correlated with tumor differentiation (P < 0.01), TNM stage (P < 0.01), and lymph node metastasis (P < 0.01). Then, functional studies demonstrate that restoration of miR-133a in HepG2 cells significantly suppressed proliferation, colony formation, migration, and invasion, induced cell cycle arrest at G0/G1 stage and cell apoptosis in vitro, and decreased tumor size and weight in a nude mouse HepG2 xenograft model. Using bioinformatics method and dual luciferase assays identified insulin-like growth factor 1 receptor (IGF-1R) as a direct target of miR-133a in HCC cells. Furthermore, overexpression of miR-133a inhibited activation AKT and ERK signal pathway, which contributed to suppression of HCC cell growth. These findings suggest that miR-133a may act as a tumor suppressor and inhibited survival of HCC cells by targeting IGF-1R.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-133"}
{"PMID":28543721,"Year":2017,"Title":"Long Non-Coding RNA MALAT1 Regulates ZEB1 Expression by Sponging miR-143-3p and Promotes Hepatocellular Carcinoma Progression.","Abstract":"Hepatocellular carcinoma (HCC) is one of the most common malignancies. Long non-coding RNAs (lncRNAs) are involved in HCC. This study aimed to explore the effects of lncRNA MALAT1 on HCC development. MALAT1, ZEB1, and miR-143-3p in HCC tissues was detected by qRT-PCR. Effect of MALAT1 on the proliferation and metastasis of HCC cells was estimated by cell-counting, wound-healing, and transwell assays. Luciferase reporter assays were used to explore miR-143-3p's target, ZEB1. QRT-PCR and Western blot were employed to determine the effects of MALAT1 or/and miR-143-3p on ZEB1 expression. MALAT1 was upregulated in HCC tissues. ZEB1 was a target of miR-143-3p. miR-143-3p binds with MALAT1, and was regulated by MALAT1. The regulation of MALAT1 on ZEB1 was mediated by miR-143-3p. Transfection with siR-MALAT1 significantly inhibited cell proliferation and invasion, while knockdown of miR-181a partially reversed these effects. Our findings suggest that MALAT1 may regulate ZEB1 expression by sponging miR-143-3p and promotes hepatocellular carcinoma progression. J. Cell. Biochem. 118: 4836-4843, 2017. (c) 2017 Wiley Periodicals, Inc.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-181"}
{"PMID":28199974,"Year":2017,"Title":"MiR-204 down-regulation elicited perturbation of a gene target signature common to human cholangiocarcinoma and gastric cancer.","Abstract":"BACKGROUND & AIMS: There is high need of novel diagnostic and prognostic tools for tumors of the digestive system, such as gastric cancer and cholangiocarcinoma. We recently found that miR-204 was deeply downregulated in gastric cancer tissues. Here we investigated whether this was common to other tumors of the digestive system and whether this elicited a miR-204-dependent gene target signature, diagnostically and therapeutically relevant. Finally, we assessed the contribution of the identified target genes to the cell cycle progression and clonogenicity of gastric cancer and cholangiocarcinoma cell lines. METHODS: We employed quantitative PCR and Affymetrix profiling for gene expression studies. In silico analysis aided us to identifying a miR-204 target signature in publicly available databases (TGCA). We employed transient transfection experiments, clonogenic assays and cell cycle profiling to evaluate the biological consequences of miR-204 perturbation. RESULTS: We identified a novel miR-204 gene target signature perturbed in gastric cancer and in cholangiocarcinoma specimens. We validated its prognostic relevance and mechanistically addressed its biological relevance in GC and CC cell lines. CONCLUSIONS: We suggest that restoring the physiological levels of miR-204 in some gastrointestinal cancers might be exploited therapeutically.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-204"}
{"PMID":21913185,"Year":2012,"Title":"Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer.","Abstract":"This study was performed to identify plasma microRNAs (miRNAs) as diagnostic biomarkers for pancreatic cancer (PCa) and to assess their supplementary role with serum CA19-9 in early identification of tumors. Plasma RNAs were extracted from 140 PCa patients, 111 chronic pancreatitis (CP) patients and 68 normal controls, and the relative abundances of seven miRNAs (miR-16, 21, 155, 181a, 181b, 196a and 210) were measured using real-time PCR. Their diagnostic utility for PCa and correlation with clinical characteristics were analyzed. All seven miRNAs were significantly aberrantly upregulated in the PCa group compared with both the CP and normal groups, between which only four miRNAs (miR-155, 181a, 181b and 196a) were significantly different. Logistic modeling proved that only miR-16 and miR-196a possessed an independent role in discriminating PCa from normal and CP. Furthermore, after including serum CA19-9 in the logistic model, the combination of miR-16, miR-196a and CA19-9 was more effective for discriminating PCa from non-PCa (normal+CP) (AUC-ROC, 0.979; sensitivity, 92.0%; specificity, 95.6%), and for discriminating PCa from CP (AUC-ROC, 0.956; sensitivity, 88.4%; specificity, 96.3%) compared with the miRNA panel (miR-16+miR-196a) or CA19-9 alone. Most significantly, the combination was effective at identification of tumors in Stage 1 (85.2%). In conclusion, plasma miRNAs were effective for distinguishing PCa from non-PCa (normal+CP). The combination of miR-16, miR-196a and CA19-9 was more effective for PCa diagnosis, especially in early tumor screening.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-196"}
{"PMID":26505678,"Year":2015,"Title":"Plasma microRNA profiles: identification of miR-744 as a novel diagnostic and prognostic biomarker in pancreatic cancer.","Abstract":"BACKGROUND: This study aims to explore novel microRNAs in plasma for screening cancer and predicting clinical outcomes in pancreatic cancer (PCa) patients using a microRNA array-based approach. METHODS: We used the Toray 3D-Gene microRNA array-based approach to compare plasma levels between PCa patients and healthy volunteers. RESULTS: (1) Six oncogenic microRNAs (miR-615-5p, -744, -575, -557, -675, and -550a) with high expression in plasma were selected. (2) By quantitative RT-PCR using plasma samples from 94 PCa patients and 68 healthy volunteers, a significantly higher level of plasma miR-744 in PCa patients than in healthy volunteers was validated in small-scale analysis (P=0.0038), two independent cohort analyses, and large-scale analysis (P<0.0001, AUC 0.8307). (3) miR-744 expression was significantly higher in PCa tissues (P=0.0069) and PCa cell lines (P=0.0074) than in normal tissues and fibroblasts, respectively. Preoperative plasma level of miR-744 was significantly reduced in postoperative samples (P=0.0063). (4) A high level of plasma miR-744, which was correlated with lymph node metastasis (P=0.0407) and recurrences (P=0.0376), was an independent poor prognostic factor of PCa patients after pancreatectomy (P=0.0007, HR 21.2 (3.17-436)). Furthermore, a high level of plasma miR-744 contributed to poorer progression-free survival of non-operable PCa patients who underwent gemcitabine-based chemotherapy (P=0.0533). Overexpression of miR-744 in PCa cells induced significant chemoresistance to gemcitabine in vitro. CONCLUSIONS: Plasma miR-744 might be useful biomarker for screening PCa, monitoring, and predicting poor prognosis and chemoresistance in PCa patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-550"}
{"PMID":30341009,"Year":2019,"Title":"Bioselection Reveals miR-99b and miR-485 as Enhancers of Adenoviral Oncolysis in Pancreatic Cancer.","Abstract":"Oncolytic viruses are designed for cancer treatment. Cell-virus interactions are key determinants for successful viral replication. Therefore, the extensive reprogramming of gene expression that occurs in tumor cells might create a hurdle for viral propagation. We used a replication-based approach of a microRNA (miRNA) adenoviral library encoding up to 243 human miRNAs as a bioselection strategy to identify miRNAs that facilitate adenoviral oncolytic activity in pancreatic ductal adenocarcinoma. We identify two miRNAs, miR-99b and miR-485, that function as enhancers of adenoviral oncolysis by improving the intra- and extracellular yield of mature virions. An increased adenoviral activity is the consequence of enhanced E1A and late viral protein expression, which is probably mediated by the downregulation of the transcriptional repressors ELF4, MDM2, and KLF8, which we identify as miR-99b or miR-485 target genes. Arming the oncolytic adenovirus ICOVIR15 with miR-99b or miR-485 enhances its fitness and its antitumoral activity. Our results demonstrate the potential of this strategy to improve oncolytic adenovirus potency, and they highlight miR-99b and miR-485 as sensitizers of adenoviral replication.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-99"}
{"PMID":23251334,"Year":2012,"Title":"SOX4 transcriptionally regulates multiple SEMA3/plexin family members and promotes tumor growth in pancreatic cancer.","Abstract":"Semaphorin signaling through Plexin frequently participates in tumorigenesis and malignant progression in various types of cancer. In particular, the role of semaphorin signaling in pancreatic ductal adenocarcinoma (PDAC) remains unexplored, despite a high likelihood of metastasis and mortality. Unlike other epithelial malignancies that often express a small number of specific genes in the Semaphorin/Plexin family, five or more are often expressed in human PDAC. Such concomitant expression of these SEMA3/Plexin family members is not a result of gene amplification, but (at least partially) from increased gene transcription activated by SOX4 de novo expressed in PDAC. Via chromatin-immunoprecipitation, luciferase promoter activity assay and electrophoresis mobility shift assay, SOX4 is demonstrated to bind to the consensus site at the promoter of each SEMA3 and Plexin gene to enhance transcription activity. Conversely, RNAi-knockdown of SOX4 in PDAC cell lines results in decreased expression of SEMA3/Plexin family members and is associated with restricted tumor growth both in vitro and in SCID mice. We further demonstrate that SOX4 levels parallel with the summed expression of SEMA3/Plexin family members (P = 0.033, NPar Kruskal-Wallis one-way analysis), which also correlates with poor survival in human PDAC (P = 0.0409, Kaplan-Meier analysis). Intriguingly, miR-129-2 and miR-335, both of which target SOX4 for degradation, are co-repressed in human PDAC cases associated with up-regulated SOX4 in a statistically significant way. In conclusion, we disclose a miR-129-2(miR-335)/SOX4/Semaphorin-Plexin regulatory axis in the tumorigenesis of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-335"}
{"PMID":22114139,"Year":2012,"Title":"MicroRNA alterations of pancreatic intraepithelial neoplasias.","Abstract":"PURPOSE: MicroRNA (miRNA) alterations are likely to contribute to the development of pancreatic cancer and may serve as markers for the early detection of pancreatic neoplasia. EXPERIMENTAL DESIGN: To identify the miRNA alterations that arise during the development of pancreatic cancer, we determined the levels of 735 miRNAs in 34 pancreatic intraepithelial neoplasias (PanIN) and 15 normal pancreatic duct samples isolated by laser capture microdissection using TaqMan miRNA microarrays. Differential expression of selected miRNAs was confirmed by FISH analysis and by quantitative real-time reverse transcription PCR (qRT-PCR) analysis of selected candidate miRNAs in an independent set of PanIN and normal duct samples. RESULTS: We identified 107 aberrantly expressed miRNAs in different PanIN grades compared with normal pancreatic duct samples and 35 aberrantly expressed miRNAs in PanIN-3 lesions compared with normal pancreatic duct samples. These differentially expressed miRNAs included those that have been previously identified as differentially expressed in pancreatic ductal adenocarcinomas (PDAC; including miR-21, miR-200a/b/c, miR-216a/b, miR-217, miR-146a, miR-155, miR-182, miR-196b, miR-203, miR-222, miR-338-3p, miR-486-3p, etc.) as well as miRNAs not previously described as differentially expressed in these lesions (miR-125b, miR-296-5p, miR-183*, miR-603, miR-625/*, miR-708, etc.). miR-196b was the most selectively differentially expressed miRNA in PanIN-3 lesions. CONCLUSIONS: Many miRNAs undergo aberrant expression in PanIN lesions and are likely to be important in the development of PDAC. The miRNAs, such as miR-196b, whose expression is limited to PanIN-3 lesions or pancreatic cancers could be useful as diagnostic markers.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-146"}
{"PMID":30985693,"Year":2019,"Title":"MicroRNA-related transcription factor regulatory networks in human colorectal cancer.","Abstract":"OBJECTIVE: Colorectal cancer (CRC) is an extremely common gastrointestinal malignancy. The present study aimed to identify microRNAs (miRNAs) and transcription factors (TFs) associated with tumor development. METHODS: Three miRNA profile datasets were integrated and analyzed to elucidate the potential key candidate miRNAs in CRC. The starBase database was used to identify the potential targets of common differentially expressed miRNAs (DEMs). Transcriptional Regulatory Element Database and Transcriptional Regulatory Relationships Unraveled by Sentence-based Text databases were used to identify cancer-related TFs and the TF-regulated target genes. Functional and pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integration Discovery (DAVID) database, and the miRNA-TF-gene networks were constructed by Cytoscape. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of genes and miRNAs. RESULTS: In total, 14 DEMs were found in CRC. By bioinformatics analysis, 5 DEMs (miR-145, miR-497, miR-30a, miR-31, and miR-20a) and 8 TFs (ELK4 (ETS-family transcription factor), myeloblastosis proto-oncogene like (MYBL)1, MYBL2, CEBPA, PPARA, PPARD, PPARG, and endothelial PAS domain protein (EPAS1)) appeared to be associated with CRC and were therefore used to construct miRNA-TF-gene networks. From the networks, we found that miR-20a might play the most important role as an miRNA in the networks. By qRT-PCR, we demonstrated that miR-20a was significantly upregulated in CRC tissues. We also performed qRT-PCR to identify the expression of miR-20a-related TFs (PPARA, PPARD, PPARG, EPAS1). Three of them, PPARA, PPARG, and EPAS1, were downregulated in CRC tissues, with statistically significant differences, while the downregulation of PPARD in CRC tissues was not significantly different. Pathway enrichment analyses indicated that the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway was the most significantly enriched pathway. Two main elements of the PI3K-Akt signaling pathway, phosphatase and tensin homolog deleted on chromosome 10 and B-cell lymphoma 2-associated agonist of cell death, were demonstrated to be downregulated in CRC. CONCLUSION: The present study identified hub miRNAs and miRNA-related TF regulatory networks in CRC, which might be potential targets for the diagnosis and treatment of CRC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-497"}
{"PMID":27630293,"Year":2016,"Title":"MEK Inhibitor Suppresses Expression of the miR-17-92 Cluster with G1-Phase Arrest in HT-29 Human Colon Cancer Cells and MIA PaCa-2 Pancreatic Cancer Cells.","Abstract":"BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs, and the deregulated expression of miRNAs is associated with tumor development. Among these, the miR-17-92 cluster, including six mature miRNAs, is known as an oncogenic miRNA cluster because expression of the miR-17-92 cluster is frequently elevated in a variety of malignant tumors. MATERIALS AND METHODS: We investigated whether a mitogen-activated protein kinase kinase (MEK) inhibitor, PD0325901, suppresses expression of the miR-17-92 cluster in HT-29 human colon cancer cells and MIA PaCa-2 pancreatic cancer cells. RESULTS: PD0325901 inhibited cell growth with G1-phase arrest and suppressed expression of the miR-17-92 cluster. Furthermore, phosphatase and tensin homolog (PTEN), which is a target molecule of the miR-17-92 cluster, was up-regulated by PD0325901. The exogenous expression of miR-17 slightly, but significantly reduced G1-phase arrest by PD0325901. CONCLUSION: These results raise the possibility that a MEK inhibitor causes G1-phase arrest, at least partially, through suppression of the miR-17-92 cluster.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-17"}
{"PMID":30226601,"Year":2018,"Title":"The interaction between miR148a and DNMT1 suppresses cell migration and invasion by reactivating tumor suppressor genes in pancreatic cancer.","Abstract":"DNA methylation is an epigenetic mechanism that cells use to control gene expression, which serves an important role in tumorigenesis. DNA methyltransferase 1 (DNMT1) is responsible for the maintenance of the pattern of DNA methylation. Overexpression of DNMT1 is observed in numerous malignant tumors, including pancreatic cancer, and results in silencing of several key tumor suppressor genes (TSGs). Recent studies have suggested that microRNAs (miRNAs/miRs) contribute to the regulation of DNMT1 expression, and promoter hypermethylation caused by DNMT1 overexpression is associated with the dysfunction of some miRNAs. The present study aimed to reveal the interaction between miR148a and DNMT1, and its effects on cell proliferation, migration and invasion of pancreatic cancer cells. Initially, the expression levels of DNMT1 and miR148a were detected in pancreatic cancer tissues and AsPC1 cells by reverse transcriptionquantitative polymerase chain reaction (PCR). Secondly, the regulatory effects of DNMT1 on miR148a were evaluated using methylationspecific PCR. Furthermore, bioinformatics analysis and dual luciferase reporter assay were used to verify the target relationship between miR148a and DNMT1. Finally, in vitro rescue experiments were conducted to evaluate the effects of miR148a on the expression of TSGs and the malignant phenotype in AsPC1 cells. The results demonstrated that DNMT1 was aberrantly upregulated in pancreatic cancer, and was responsible for hypermethylation of the miR148a promoter. Furthermore, DNMT1 was revealed as a direct target of miR148a by dual luciferase reporter assay, and restoration of miR148a could reactivate TSGs, such as p16, preproenkephalin and Ras association domain family member 1 by targeting DNMT1 in the AsPC1 pancreatic cancer cell line. These results indicated that an interaction exists between miR148a and DNMT1 in pancreatic cancer. Notably, miR148a overexpression significantly inhibited cell proliferation, migration and invasion in AsPC1 cells. Therefore, miR148a may serve as a novel therapeutic target for the treatment of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-148"}
{"PMID":29260513,"Year":2017,"Title":"[The Study of Methylated Regulation MicroRNA in Pancreatic Carcinoma Cell and Its Effect on Cell Proliferation,Migration and Invasion].","Abstract":"OBJECTIVE: To study the epigenetic regulation of pancreatic carcinoma related microRNA (miR34a,miR34b,miR148a and miR203a) expression by gene promoter methylation,and its effect on the proliferation,migration and invasion of pancreatic carcinoma cells. METHODS: The pancreatic carcinoma cells were divided into two groups:control group and treatment group.Control group was treated with 0 mumol/L DNA methyltransferase inhibitor 5-Aza-CdR and treatment group was treated with 60 mumol/L 5-Aza-CdR. The methylation status of microRNA gene promoter regions was detected by MSP (methylation-specific PCR). The microRNAs' expression levels were evaluated by real-time PCR. The CCK-8 assay,wound healing assay and Transwell assay were employed to study the proliferation,migration and invasion of pancreatic carcinoma cells,respectively. RESULTS: The results of MSP showed that the methylated band of the treated group was weaker than that of the untreated group and the unmethylated band of the treated group was stronger than that of the untreated group. Real-time PCR results showed that the relative expression levels of microRNAs in the treatment group were higher than those in the control group ( P<0.05). The CCK-8 assay showed that inhibition rate of the treatment group showed dose-dependent effect with the increase of drug concentration. Wound healing assay showed that the wound healing rate of Treatment group was lower than that of untreated group ( P<0.01). The results of transwell assay showed that the number of migrated cells in the treated group was less than that in the untreated group ( P<0.01). CONCLUSION: Decreased methylation levels in microRNA promoter region caused by 5-Aza-CdR treatment increased the expression of miR34a,miR34b ,miR148a and miR203a,leading to inhibition of the proliferation,migration and invasion of pancreatic carcinoma cells.","Language":"chi","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-203"}
{"PMID":24294832,"Year":2014,"Title":"The zinc transporter LIV-1 is a novel regulator of stemness in pancreatic cancer cells.","Abstract":"OBJECTIVE: Recent studies have identified the existence a portion of cancer cells, called \"cancer stem cells\", within the entire cancer tissue. Cancer stem cells harbor highly tumorigenic and chemo-resistant phenotypes, which lead to recurrence or re-growth of the tumor after surgery. The mechanisms that regulate the stemness of cancer cells remain largely unknown. We hypothesized that LIV-1, a zinc transporter, regulates the stemness in pancreatic cancer cells. MATERIAL AND METHODS: We established two stable Panc-1 pancreatic cancer cell lines in which LIV-1 expression was knocked down by the introduction of siRNA against LIV-1. Expression of cancer stem cell-related molecules was examined by quantitative real-time PCR. Expression of ATP-binding cassette sub-family G member 2 was also determined by flow cytometry. Spheroid culture was performed in low-adhesion coated plates. Cell migration was determined by using a modified 2-chamber migration assay. In vivo tumor formation was assessed in nude mice after the subcutaneous injection of cancer cells. The Agilent's miRNA microarray was used to identify differentially expressed miRNAs. RESULTS: Knockdown of LIV-1 expression resulted in (i) decreased expression of cancer stem cell-related molecules such as LIN28 and ATP-binding cassette sub-family G member 2, (ii) decreased spheroid-forming ability, (iii) decreased migration, (iv) decreased incidence of tumor formation in nude mice, and (v) upregulation of miR-7 expression. CONCLUSIONS: Our results suggest that LIV-1 might act as a novel regulator of stemness in pancreatic cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-7"}
{"PMID":29295989,"Year":2018,"Title":"Amphiphilic nanocarrier-induced modulation of PLK1 and miR-34a leads to improved therapeutic response in pancreatic cancer.","Abstract":"The heterogeneity of pancreatic ductal adenocarcinoma (PDAC) suggests that successful treatment might rely on simultaneous targeting of multiple genes, which can be achieved by RNA interference-based therapeutic strategies. Here we show a potent combination of microRNA and siRNA delivered by an efficient nanocarrier to PDAC tumors. Using proteomic-microRNA profiles and survival data of PDAC patients from TCGA, we found a novel signature for prolonged survival. Accordingly, we used a microRNA-mimic to increase miR-34a together with siRNA to silence PLK1 oncogene. For in vivo dual-targeting of this combination, we developed a biodegradable amphiphilic polyglutamate amine polymeric nanocarrier (APA). APA-miRNA-siRNA polyplexes systemically administered to orthotopically inoculated PDAC-bearing mice showed no toxicity and accumulated at the tumor, resulting in an enhanced antitumor effect due to inhibition of MYC oncogene, a common target of both miR-34a and PLK1. Taken together, our findings warrant this unique combined polyplex's potential as a novel nanotherapeutic for PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-34"}
{"PMID":31006985,"Year":2019,"Title":"Identification of a six-miRNA panel in serum benefiting pancreatic cancer diagnosis.","Abstract":"Pancreatic cancer (PC) has posed a great health threat to a growing number of people all over the world. Detection of serum miRNAs, being sensitive, noninvasive, and easy to obtain, has a great potential of being a novel screening method for PC patients. In this study, we investigated miRNA expression levels in serum by qRT-PCR. The study was divided into four phases: the screening, training, testing, and external validation stage. We firstly chose candidate miRNAs using Exiqon panels in the screening phase. Then, a total of 129 PC serum samples and 107 normal controls (NCs) were further analyzed in the following training and testing phases to identify differently expressed miRNAs. A cohort of 30 PC serum samples vs 30 NCs was used to confirm the diagnostic value of the identified miRNAs in the external validation phase. Moreover, miRNA expressions in additional 44 PC tumor tissue samples and the matched adjacent normal tissue samples as well as 32 pairs of serum-derived exosomes samples were also further explored. As a result, we identified six significantly upregulated miRNAs in the serum of PC: let-7b-5p, miR-192-5p, miR-19a-3p, miR-19b-3p, miR-223-3p, and miR-25-3p. A six-miRNA panel in serum was then established. The area under the receiver operating characteristic curves (AUC) for the panel was 0.910 for the combined training and testing phases, which showed higher diagnostic value than the individual miRNA. Prognostic value prediction using Cox's proportional hazards model and Kaplan-Meier curves showed that increased serum miR-19a-3p was closely related to worse overall survival (OS). In addition, significant upregulation of miR-192-5p, miR-19a-3p, and miR-19b-3p was observed in both PC tissue and serum-derived exosomes samples. In conclusion, we identified a six-miRNA (let-7b-5p, miR-192-5p, miR-19a-3p, miR-19b-3p, miR-223-3p, and miR-25-3p) panel in the serum for PC early and noninvasive diagnosis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-19"}
{"PMID":28534950,"Year":2017,"Title":"MicroRNA296 targets AKT2 in pancreatic cancer and functions as a potential tumor suppressor.","Abstract":"Although microRNA-296 (miR-296) has been studied in various types of human cancer, its expression, biological role and mechanism of action in pancreatic cancer remains to be elucidated. The aim of the current study was to investigate the expression level, possible roles and underlying molecular mechanisms of miR296 in pancreatic cancer. The present study revealed that miR296 is significantly downregulated in tissue from patients with pancreatic cancer and in human pancreatic carcinoma cell lines, when compared with matched healthy tissue and normal human pancreatic cell lines, respectively. In addition, restoration of miR296 expression was revealed to inhibit the proliferation, migration and invasive activity of pancreatic cancer cells. Furthermore, bioinformatics analysis and a luciferase reporter assay validated the AKT2 gene as a direct target of miR296 in pancreatic cancer. Reverse transcriptionquantitative polymerase chain reaction and western blot analysis revealed that miR296 was able to decrease AKT2 expression at the posttranscriptional level. Notably, the effects of AKT2 knockdown were similar to miR296 overexpression in pancreatic cancer. In conclusion, the present findings indicate a role for miR296 as a tumor suppressor in pancreatic cancer through directly targeting AKT2, thus suggesting that miR296 may serve as a potential therapeutic target for the treatment of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-296"}
{"PMID":26530325,"Year":2016,"Title":"MicroRNA-148b targets Rho-associated protein kinase 1 to inhibit cell proliferation, migration and invasion in hepatocellular carcinoma.","Abstract":"microRNA(miR)-148b has been found to be downregulated in various human malignancies, including hepatocellular carcinoma (HCC) as well as gastric, pancreatic, colon and oral cancer. However, the function of miR148b in HCC has remained elusive. The present study examined the effects of miR148b on the proliferation, migration and invasion of HCC cells in vitro. After transfection of the HepG2 and SMMC7721 HCC cell lines with miR148b, an MTT assay, a Transwell migration and invasion assay as well as western blot analysis were performed. miR-148b was shown to inhibit cell proliferation, migration and invasion in the two cell lines. Using a luciferase reporter assay, the present study also provided the first evidence that miR148b directly targets Rhoassociated protein kinase 1 in HCC. These results suggested that miR-148 may represent a novel molecular marker and a potential molecular therapeutic for inhibiting metastasis of HCC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-148"}
{"PMID":29169171,"Year":2017,"Title":"MiRNAs are Unlikely to be Involved in Retinoid Receptor Gene Regulation in Pancreatic Cancer Cells.","Abstract":"BACKGROUND/AIMS: Retinoid receptors and retinoic acid were reported to be down-regulated in pancreatic duct adenocarcinoma (PDAC) compared to normal pancreas. Yet the mechanism of the down-regulation of retinoid receptors is not well defined. The aim of this study was to find out whether selected dysregulated miRNAs in PDAC are responsible for the decreased level of retinoid receptors. METHODS: Bioinformatics, real-time PCR, western blot analysis as well as molecular manipulation with miRNA in cells of PDAC were carried out. RESULTS: We first performed bioinformatics research to identify conserved target sequences for deregulated miRNAs within the 3'UTR region of retinoid receptor mRNA. This research revealed binding sites for miR-138, -27a, -27b, -206, -613, -9-5p, -27a/b-3p and -27a. Next, we investigated the expression of selected retinoid receptors and miRNAs in PDAC cell lines and in the Human Pancreatic Duct Epithelial (HPDE) cell line. Further, we investigated the effects of modifying expression levels of selected miRNAs using miRNA inhibitors or mimics. We demonstrated that none of these miRNAs can target the selected retinoid receptors in vitro. CONCLUSIONS: miR-27a, miR-27b, miR-9, miR10a and miR-10b were up-regulated in PDAC cells compared to HPDE cells. The up-regulation of these miRNAs was not responsible for the down-regulation of RARalpha, RARbeta, RXRalpha and RXRbeta in PDAC cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-138"}
{"PMID":26094174,"Year":2015,"Title":"Housekeeping genes for studies of plasma microRNA: A need for more precise standardization.","Abstract":"INTRODUCTION: Plasma microRNAs (miRNAs) are promising biomarkers for many forms of cancer in humans; however, a fundamental concern is the lack of standardization in current data acquisition and reporting. Part of this problem lies in the use of numerous, different housekeeping genes (HKG) for the acquisition of real-time polymerase chain reaction data. This existing practice of using different HKGs generally is accepted, but reproducibility of data for comparison and validation between different laboratories calls for improvement. The need for data reproducibility standardization is crucial. An ideal plasma HKG (1) should be expressed in all samples, (2) have medium-to-high levels of expression, and (3) have consistently measurable levels of expression. METHODS: Total RNA was extracted from 200-muL plasma samples via a modified miRNeasy (QIAGEN) extraction technique with yeast carrier. Total RNA purity was assessed with a Nanodrop 2000 spectrophotometer (Thermo Scientific). The cycle threshold (Ct) was fixed at 0.03 for all samples. We investigated 10 potential HKGs based both on reports in the literature and our previous data. The potential HKGs were Let-7a, Let-7d, Let-7g, miR-16, RNU6, RNU48, miR-191, miR-223, miR-484, and miR-520d-5p. Once all samples were run for each potential HKG, the mean Ct and SD was calculated for all sample groups, allowing for comparison among HKGs. RESULTS: We screened 380 miRNAs by using microfluidic array technology (Applied Biosystems) in a discovery cohort of 20 colorectal cancer (CRC) patients, 10 patients each with breast cancer (BC), lung cancer (LC), pancreatic cancer (PC), 11 patients with colorectal adenoma, and 12 controls. The mean Ct and SD was calculated for RNU6, miR-520d-5p, miR-16, miR-191, miR-223, and miR-484, which were expressed in all samples. Let-7a, Let-7d, Let-7g, and RNU48 were only expressed in 26%, 7%, 10%, and 8% of samples, respectively, and therefore were deemed to be insufficiently reliable HKGs. Only miRNAs with >50% expression were included in this statistical analysis. U6 and miR-520d-5p had the most consistent Ct as well as the least SD. The use of both RNU6 and 520d-5p as HKGs provided reliable results. CONCLUSION: Among HKGs that were expressed in all samples, we suggest that RNU6 and miR-520d-5p were the best candidates for HKGs for studies of plasma miRNA because of the consistent and high Ct in all samples and a very narrow, reproducible SD.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-484"}
{"PMID":25520858,"Year":2014,"Title":"MicroRNAs in stool samples as potential screening biomarkers for pancreatic ductal adenocarcinoma cancer.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90-95% exocrine malignant tumors of the pancreas. The high prevalence of metastasis and the difficulty of early diagnosis lead to a dismal prognosis. MicroRNAs (miRNAs) play a critical role in extensive biological processes. The purpose of this study was to evaluate the feasibility of stool miRNAs as novel biomarker for PDAC screening. MiRNAs were extracted from clinical specimens which included cancer and matched adjacent benign pancreatic tissues of 30 PDAC patients, pancreatic juice of 20 from the 30 PDAC patients and 10 chronic pancreatitis (CP) patients, stool samples of the 30 PDAC patients, the 10 CP patients and 15 healthy volunteers. Relative expression of a panel of 5 dysregulated miRNAs (miR-21, miR-155, miR-196a, miR-216 and miR-217) was analyzed with qRT-PCR. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool miRNAs in PDAC patients. The study showed that our methods of extracting and detecting miRNAs from pancreatic juice and stool specimens had high reproducibility. Compared to matched adjacent benign pancreatic tissues and pancreatic juice of CP patients, the expression of miR-21 (P = 0.0021 and P = 0.0027) as well as miR-155 (P = 0.0087 and P = 0.0067) was significantly higher and the expression of miR-216 (P < 0.0001 and P = 0.0044) was significantly lower in primary tumor tissues and pancreatic juice of PDAC patients. PDAC patients had a significantly higher stool miR-21 and miR-155 (P = 0.0049 and P = 0.0112) and lower miR-216 level (P = 0.0002) compared to normal controls. The same results were obtained in the expression levels of stool miR-21, miR-155 and miR-216 between PDAC and CP patients (P = 0.0337, P = 0.0388 and P = 0.0117, respectively). Receiver operating characteristic (ROC) analysis by using stool miRNAs expression indicated that combination of miR-21 and miR-155 had best sensitivity of 93.33% while the combination of miR-21, miR-155 and miR-216 would be best for detecting and screening PDAC with area under the curve (AUC) of 0.8667 (95% CI: 0.7722-0.9612) and a better balance of sensitivity and specificity (83.33% vs. 83.33%). Our data indicate that miRNAs could be extracted and detected from pancreatic juice and stool efficiently and reproducibly. MiR-21, miR-155 and miR-216 in stool have the potential of becoming biomarkers for screening PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-196"}
{"PMID":28638102,"Year":2017,"Title":"miR-509-5p and miR-1243 increase the sensitivity to gemcitabine by inhibiting epithelial-mesenchymal transition in pancreatic cancer.","Abstract":"The epithelial-mesenchymal transition (EMT) contributes to various processes in cancer progression, such as metastasis and drug resistance. Since we have already established a cell-based reporter system for identifying EMT-suppressive microRNAs (miRNAs) in the pancreatic cancer cell line Panc1, we performed a function-based screening assay by combining this reporter system and a miRNA library composed of 1,090 miRNAs. As a result, we identified miR-509-5p and miR-1243 as EMT-suppressive miRNAs, although the mechanisms for EMT-suppression induced by these miRNAs have yet to be clarified. Herein, we demonstrated that overexpression of miR-509-5p and miR-1243 increased the expression of E-cadherin through the suppression of EMT-related gene expression and that drug sensitivity increased with a combination of each of these miRNAs and gemcitabine. Moreover, miR-509-5p was associated with worse overall survival in patients with pancreatic cancer and was identified as an independently selected predictor of mortality. Our findings suggest that miR-509-5p and miR-1243 might be novel chemotherapeutic targets and serve as biomarkers in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1243"}
{"PMID":28938522,"Year":2017,"Title":"miR-539 inhibits human colorectal cancer progression by targeting RUNX2.","Abstract":"Emerging evidence has shown that microRNAs (miRNAs) such as miR-539 play critical roles in carcinogenesis and progression in many types of cancer, including human colorectal cancer (CRC). However, the roles and underlying mechanism of miR-539 in CRC have not been well identified. The aims of this study were, therefore, to investigate the regulatory role and potential mechanism of miR-539 in human CRC. Here, we show that miR-539 expression is downregulated in CRC tissues and cell lines. The expression level of miR-539 is inversely associated with advanced clinical stage and lymph node metastasis. In vitro studies reveal that overexpression of miR-539 inhibits CRC cell proliferation and colony formation as well as migration and invasion; in vivo results demonstrate that overexpression of miR-539 dramatically reduces CRC xenograft tumor growth. Moreover, runt-related transcription factor 2 (RUNX2), a known oncogene, was identified as a target transcript of miR-539 in CRC by bioinformatic analysis, luciferase reporter assay, qPCR, and western blotting. RUNX2 expression levels were upregulated and inversely correlated with miR-539 expression in CRC tissues. Importantly, overexpression of RUNX2 without the 3'-untranslated region that is targeted by miR-539 partially reversed the inhibitory effect of miR-539 on CRC cell proliferation, migration, and invasion. Collectively, these findings demonstrate that miR-539 functions as a tumor suppressor in CRC, at least in part, by targeting RUNX2, supporting the targeting of the novel miR-539 as a potentially effective therapeutic approach for treatment of CRC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-539"}
{"PMID":25350767,"Year":2014,"Title":"A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile.","Abstract":"OBJECTIVES: Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls. METHODS: We identified patients (n=215) with treatment-naive PDAC (n=77), CP with bile/pancreatic duct pathology (n=67), and controls (n=71) who had been prospectively enrolled in a Pancreatobiliary Biorepository at the time of endoscopic retrograde cholangiopancreatography or endoscopic ultrasound. Controls were patients with choledocholithiasis but normal pancreata. The sample was separated into training (n=95) and validation (n=120) cohorts to establish and then test the performance of PDAC Signature Panels in diagnosing PDAC. The training cohort (n=95) included age-matched patients with PDAC, CP, and controls. Panels were derived from the differential expression of 10 candidate miRNAs in plasma or bile. We selected miRNAs having excellent accuracy for inclusion in regression models. RESULTS: Using the training cohort, we confirmed the differential expression of 9/10 miRNAs in plasma (miR-10b, -30c, -106b, -132, -155, -181a, -181b, -196a, and -212) and 7/10 in bile (excluding miR-21, -132, and -181b). Of these, five (miR-10b, -155, -106b, -30c, and -212) had excellent accuracy for distinguishing PDAC. In the training and validation cohorts, the sensitivity/specificity for a PDAC Panel derived from plasma was 95/100% and 100/100%, respectively; in bile, these were 96/100% and 100/100%. CONCLUSIONS: Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC. Additional studies are needed to confirm this Panel and explore its value as a prognostic test.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-181"}
{"PMID":27380024,"Year":2016,"Title":"Specific MAPK-Associated MicroRNAs in Serum Differentiate Pancreatic Cancer from Autoimmune Pancreatitis.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is difficult to distinguish from autoimmune pancreatitis (AIP) because of their clinical and radiological similarities, and therefore simple and minimally invasive surrogate markers for differential diagnosis would be useful. In our previous studies, we identified four microRNAs (miRNAs)-miR-7, miR-34a, miR-181d, and miR-193b -as MAPK-associated microRNAs whose expression was altered significantly with upregulation of the MAPK signaling pathway. Recently it has been reported that these miRNAs could be used as biomarkers in serum samples for accurate diagnosis of pancreatic lesions. The aim of the present study was to evaluate whether these MAPK-associated miRNAs in serum could be used as biomarkers for differentiating PDAC from AIP. We enrolled 69 patients with PDAC, 26 with intraductal papillary mucinous neoplasm (IPMN) and 15 with AIP. The expression of MAPK-associated miRNAs in serum was measured by quantitative real-time PCR. The 2-DeltaCT method was used to quantify the expression of miRNAs, and the data were normalized using spiked-in synthetic cel-miR-39. Patients with PDAC or IPMN showed significantly higher amounts of serum MAPK-associated miRNAs than those with AIP (p<0.009 for miR-7, p<0.002 for miR-34a, p<0.001 for miR-181d, p<0.002 for miR-193b). ROC curve analysis demonstrated that these miRNAs had an area under the ROC curve (AUC) of 0.723-0.882 for differentiation between PDAC or IPMN from AIP. Furthermore, serum miR-181d was significantly associated with the presence of metastasis in patients with PDA (p = 0.014). Serum MAPK-associated miRNAs could be novel noninvasive biomarkers for differentiation between PDAC or IPMN and AIP.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-181"}
{"PMID":26940738,"Year":2016,"Title":"miR-1271 inhibits migration, invasion and epithelial-mesenchymal transition by targeting ZEB1 and TWIST1 in pancreatic cancer cells.","Abstract":"Pancreatic cancer (PC) remains one of the most lethal types of cancer in adults. The purpose of this study was to determine the role of miR-1271 in regulation of epithelial mesenchymal transition (EMT) and metastasis of pancreatic cancer cells. miR-1271 was identified to be significantly down-regulated in PC tissues by miRNA array. Also, an increase of EMT-regulators ZEB1 and TWIST1 expression level is accompanied by a decrease of miR-1271. We showed that expression of miR-1271 was significantly down-regulated in PC tissues as compared with that in normal tissues. In addition, our results showed that miR-1271 expression levels were decreased while ZEB1 and TWIST1 expression levels were increased in detected PC cell lines. Moreover, ectopic expression of miR-1271 suppressed and antagomiR-1271 promoted proliferation, migration, and invasion in SW1990 and PANC-1 cells. Bioinformatics coupled with luciferase and Western blot assays also revealed that miR-1271 inhibited expression of ZEB1 and TWIST1, which are master regulators of tumor metastasis. Our study first indicates that miR-1271 functions as a suppressor in regulating of pancreatic cancer EMT by targeting ZEB1 and TWIST1, and it promise as a therapeutic target and prognostic marker for metastatic pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1271"}
{"PMID":26918939,"Year":2016,"Title":"MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor.","Abstract":"Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs and TGF-beta-activated human PSCs (hPSCs). Inhibition of miR-199a/-214 using hairpin inhibitors significantly inhibited TGFbeta-induced differentiation markers (e.g. alpha-SMA, collagen, PDGFbetaR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs attained smaller size with hPSCs transfected with anti-miR-199a/-214 compared to control anti-miR. The conditioned medium obtained from TGFbeta-activated hPSCs induced tumor cell growth and endothelial cell tube formation. Interestingly, these inductions were abrogated in hPSCs transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-199"}
{"PMID":26272168,"Year":2015,"Title":"A miR-130a-YAP positive feedback loop promotes organ size and tumorigenesis.","Abstract":"Organ size determination is one of the most intriguing unsolved mysteries in biology. Aberrant activation of the major effector and transcription co-activator YAP in the Hippo pathway causes drastic organ enlargement in development and underlies tumorigenesis in many human cancers. However, how robust YAP activation is achieved during organ size control remains elusive. Here we report that the YAP signaling is sustained through a novel microRNA-dependent positive feedback loop. miR-130a, which is directly induced by YAP, could effectively repress VGLL4, an inhibitor of YAP activity, thereby amplifying the YAP signals. Inhibition of miR-130a reversed liver size enlargement induced by Hippo pathway inactivation and blocked YAP-induced tumorigenesis. Furthermore, the Drosophila Hippo pathway target bantam functionally mimics miR-130a by repressing the VGLL4 homolog SdBP/Tgi. These findings reveal an evolutionarily conserved positive feedback mechanism underlying robustness of the Hippo pathway in size control and tumorigenesis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-130"}
{"PMID":22045190,"Year":2011,"Title":"Novel diagnostic value of circulating miR-18a in plasma of patients with pancreatic cancer.","Abstract":"BACKGROUND: Several recent studies have demonstrated that microRNAs (miRNAs) are stably detectable in the plasma/serum. We hypothesised that miR-18a in the plasma is a potential biomarker in patients with pancreatic cancer. METHODS: miR-18a is located in the miR-17-92 cluster and reported to be highly expressed in pancreatic cancer tissues. This study was divided into three parts: (1) Confirmation of higher miR-18a levels in primary pancreatic cancer tissues and cell lines than in normal pancreatic tissues and a human fibroblast cell line. (2) Evaluation of the plasma miR-18a assay using quantitative RT-PCR by comparing plasma results obtained from 36 patients with pancreatic cancer and from 30 healthy volunteers. (3) Evaluation of the assay for monitoring tumour dynamics in patients with pancreatic cancer. RESULTS: (1) The expression of miR-18a was significantly higher in pancreatic cancer tissues (P=0.012) and pancreatic cancer cell lines (P=0.015) than in normal tissues and fibroblasts. (2) Plasma concentrations of miR-18a were significantly higher in pancreatic cancer patients than in controls (P<0.0001). The value of the area under the receiver-operating characteristic curve (AUC) was 0.9369. (3) Plasma levels of miR-18a were significantly lower in postoperative samples than in preoperative samples (P=0.0077). CONCLUSION: Circulating miR-18a might provide new complementary tumour markers for pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-18"}
{"PMID":30026054,"Year":2018,"Title":"Dysregulation of miRNA in chronic hepatitis B is associated with hepatocellular carcinoma risk after nucleos(t)ide analogue treatment.","Abstract":"Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). Nucleos(t)ide analogue (NA) therapy effectively reduces the incidence of HCC, but it does not completely prevent the disease. Here, we show that dysregulation of microRNAs (miRNAs) is involved in post-NA HCC development. We divided chronic hepatitis B (CHB) patients who received NA therapy into two groups: 1) those who did not develop HCC during the follow-up period after NA therapy (no-HCC group) and 2) those who did (HCC group). miRNA expression profiles were significantly altered in CHB tissues as compared to normal liver, and the HCC group showed greater alteration than the no-HCC group. NA treatment restored the miRNA expression profiles to near-normal in the no-HCC group, but it was less effective in the HCC group. A number of miRNAs implicated in HCC, including miR-101, miR-140, miR-152, miR-199a-3p, and let-7g, were downregulated in CHB. Moreover, we identified CDK7 and TACC2 as novel target genes of miR-199a-3p. Our results suggest that altered miRNA expression in CHB contributes to HCC development, and that improvement of miRNA expression after NA treatment is associated with reduced HCC risk.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-140"}
{"PMID":26819679,"Year":2015,"Title":"Differential Expression of MicroRNAs in Tissues and Plasma Co-exists as a Biomarker for Pancreatic Cancer.","Abstract":"OBJECTIVE: Pancreatic cancer (PC) is a lethal disease with disappointing results from current treatment modalities, suggesting that novel therapeutic strategies are urgently needed. Since microRNAs (miRNAs) are important player in biology, the clinical utility of miRNAs for designing novel therapeutics is an active area of research. The objective of the present study was to examine differentially expressed miRNAs between normal and tumor tissues, and in plasma samples obtained from PC patients, chronic pancreatitis (CP) patients and healthy subjects (HC). MATERIAL AND METHODS: The miRNA expression profiling using formalin-fixed paraffin embedded (FFPE) tissues from normal and tumor specimens was accomplished using miRBase version 19 (LC Sciences, Houston, TX, USA). Quantitative real-time PCR (qRT-PCR) was subsequently performed in individual samples for 7 selected miRNAs. In addition, qRT-PCR was also performed for assessing the expression of 8 selected miRNAs in plasma samples. RESULTS: A significant difference in the expressions of miR-21, miR-205, miR-155, miR-31, miR-203, miR-214 and miR-129-2 were found in tumor tissue samples. Lower expression of miR-214 was found to be associated with better overall survival. We also observed differential expression of 8 miRNAs in plasma samples of CP and PC patients compared to HC. Interestingly, over expression of miR-21, and miR-31 was noted in both tumor tissues and in the plasma. CONCLUSION: We found deregulated expression of miRNAs that could distinguish normal from PC in two different types of samples (tissues and plasma). Interestingly, lower expression of miR-214 was found to be associated with better overall survival. Although not statistically significant, we also observed higher expression of let-7a and lower expression of miR-508 to be associated with overall better survival. We conclude that our study nicely lays the foundation for detailed future investigations for assessing the role of these miRNAs in the pathology of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-129"}
{"PMID":28542740,"Year":2017,"Title":"Plasma microRNAs as biomarkers of pancreatic cancer risk in a prospective cohort study.","Abstract":"Noninvasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case-control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate prediagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR-10a, -10b, -21-3p, -21-5p, -30c, -106b, -155 and -212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status and age/date/time of blood collection. MiR levels in prediagnostic plasma samples were determined by quantitative RT-PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR-10b, -21-5p, -30c and -106b levels were significantly higher in cases diagnosed within 2 years of blood collection compared to matched controls (all p-values <0.04). Based on adjusted logistic regression models, levels for six miRs (miR-10a, -10b, -21-5p, -30c, -155 and -212) overall, and for four miRs (-10a, -10b, -21-5p and -30c) at shorter follow-up time between blood collection and diagnosis (<\/=5 yr, <\/=2 yr), were statistically significantly associated with risk. A score based on the panel showed a linear dose-response trend with risk (p-value = 0.0006). For shorter follow-up (<\/=5 yr), AUC for the score was 0.73, and for individual miRs ranged from 0.73 (miR-212) to 0.79 (miR-21-5p).","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-30"}
{"PMID":24555977,"Year":2014,"Title":"MicroRNA profiling in periampullary carcinoma.","Abstract":"BACKGROUND: MicroRNA expression patterns in many physiological and oncogenic processes have been established. However, the role of aberrant miRNA expression in periampullary carcinoma (PAC) has not been elucidated. We hypothesize that PAC may have differential expression of miRNAs which may differentiate the tumor histological subtypes. METHODS: Fresh paired tumor and control samples were collected from the PAC patients undergoing Whipple's pancreaticoduodenectomy. Microarray miRNA profiling was performed utilizing tumor (n = 40) and control tissues; adjacent normal pancreas (n = 22), six each distal CBD, duodenum and ampulla. Data obtained was subjected to statistical and bioinformatic analysis. Differentially expressed miRNAs obtained were validated using qPCR in an independent set of samples. RESULTS: Comparison of PAC tissue samples with controls revealed 29 common and differentially expressed miRNAs (20 upregulated and 9 downregulated) with a higher statistical significance (p < 0.001) and fold change (log2 FC > 1.5). A subset of 16 miRNAs (15 overexpressed and 1 underexpressed) differed in expression levels between pancreatobiliary and intestinal subtypes. Among these, miR-375, miR-31 and miR-196a expressions varied significantly between histological subtypes. Differential expression profiles of miRNAs specific to TNM staging was also observed in PAC subtypes. Target gene prediction for the differentially expressed miRNAs in PAC revealed that target genes are enriched for certain pathways. Particularly, Wnt signaling pathway genes appear to be relevant targets for most of the differentially expressed miRNAs. CONCLUSION: Differentially expressed common miRNA signatures identified in PAC subgroups may have a role in pathogenesis of PAC and miR-375, miR-31 and miR-196a expression patterns may differentiate PAC subtypes.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-196"}
{"PMID":21913185,"Year":2012,"Title":"Combination of plasma microRNAs with serum CA19-9 for early detection of pancreatic cancer.","Abstract":"This study was performed to identify plasma microRNAs (miRNAs) as diagnostic biomarkers for pancreatic cancer (PCa) and to assess their supplementary role with serum CA19-9 in early identification of tumors. Plasma RNAs were extracted from 140 PCa patients, 111 chronic pancreatitis (CP) patients and 68 normal controls, and the relative abundances of seven miRNAs (miR-16, 21, 155, 181a, 181b, 196a and 210) were measured using real-time PCR. Their diagnostic utility for PCa and correlation with clinical characteristics were analyzed. All seven miRNAs were significantly aberrantly upregulated in the PCa group compared with both the CP and normal groups, between which only four miRNAs (miR-155, 181a, 181b and 196a) were significantly different. Logistic modeling proved that only miR-16 and miR-196a possessed an independent role in discriminating PCa from normal and CP. Furthermore, after including serum CA19-9 in the logistic model, the combination of miR-16, miR-196a and CA19-9 was more effective for discriminating PCa from non-PCa (normal+CP) (AUC-ROC, 0.979; sensitivity, 92.0%; specificity, 95.6%), and for discriminating PCa from CP (AUC-ROC, 0.956; sensitivity, 88.4%; specificity, 96.3%) compared with the miRNA panel (miR-16+miR-196a) or CA19-9 alone. Most significantly, the combination was effective at identification of tumors in Stage 1 (85.2%). In conclusion, plasma miRNAs were effective for distinguishing PCa from non-PCa (normal+CP). The combination of miR-16, miR-196a and CA19-9 was more effective for PCa diagnosis, especially in early tumor screening.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-16"}
{"PMID":26036346,"Year":2015,"Title":"Micro-RNAs miR-29a and miR-330-5p function as tumor suppressors by targeting the MUC1 mucin in pancreatic cancer cells.","Abstract":"MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To control cancer progression, miRNAs became very recently, major targets and tools to inhibit oncogene expression. Inhibiting MUC1 using miRNAs appears thus as an attractive strategy to reduce cancer progression. However, potent miRNAs and associated mechanisms regulating MUC1 expression remain to be identified. To this aim, we undertook to study MUC1 regulation by miRNAs in pancreatic cancer cells and identify those with tumor suppressive activity. MiRNAs potentially targeting the 3'-UTR, the coding region, or the 5'-UTR of MUC1 were selected using an in silico approach. Our in vitro and in vivo experiments indicate that miR-29a and miR-330-5p are strong inhibitors of MUC1 expression in pancreatic cancer cells through direct binding to MUC1 3'-UTR. MUC1 regulation by the other selected miRNAs (miR-183, miR-200a, miR-876-3p and miR-939) was found to be indirect. MiR-29a and miR-330-5p are also deregulated in human pancreatic cancer cell lines and tissues and in pancreatic tissues of Kras(G12D) mice. In vitro, miR-29a and miR-330-5p inhibit cell proliferation, cell migration, cell invasion and sensitize pancreatic cancer cells to gemcitabine. In vivo intra-tumoral injection of these two miRNAs in xenografted pancreatic tumors led to reduced tumor growth. Altogether, we have identified miR-29a and miR-330-5p as two new tumor suppressive miRNAs that inhibit the expression of MUC1 oncogenic mucin in pancreatic cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-29"}
{"PMID":28315290,"Year":2017,"Title":"UCA1 Regulates the Growth and Metastasis of Pancreatic Cancer by Sponging miR-135a.","Abstract":"Pancreatic cancer (PC) is a devastating malignant disease with a poor prognosis. This study aimed to investigate the role of urothelial carcinoma associated 1 (UCA1) in the progression of PC. Our results revealed that long noncoding RNA (lncRNA) UCA1 was overexpressed in PC tissues compared with adjacent histologically normal tissues. A downregulated level of UCA1 was also detected in five human PC cell lines (SW1990, BxPC-3, MiaPaCa-2, PANC-1, and CAPAN-1) compared with normal pancreatic duct epithelial HPDE cells. The proliferation of PC cells was inhibited after UCA1 was suppressed by a lentiviral vector. The cell apoptosis rate was largely promoted by downregulating UCA1. Further research revealed that microRNA (miRNA)-135a is a direct target of UCA1. The expression of miR-135a was decreased in PC tissues and cell lines compared with control groups. In addition, the decreased level of miR-135a was elevated by adding miR-135a mimic in SW1990 cells transfected with lncRNA UCA1. Similarly, an upregulated level of miR-135a was downregulated by adding miR-135a inhibitor in SW1990 cells transfected with UCA1 siRNA. Luciferase activity assay further confirmed the targeting relationship between UCA1 and miR-135a. Moreover, miR-135a reversed the effect of UCA1 on cell apoptosis rate and cell viability in SW1990 cells. The migration and invasion capacities of PC cells were suppressed by UCA1. siRNA was then enhanced by the miR-135a inhibitor. In vivo, UCA1 siRNA effectively suppressed tumor growth and the expression of migration markers. Taken together, our research revealed that UCA1 works as an oncogene by targeting miR-135a. The UCA1-miR-135a pathway regulated the growth and metastasis of PC, providing new insight in the treatment of PC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-135"}
{"PMID":26284487,"Year":2015,"Title":"Simultaneous inhibition of multiple oncogenic miRNAs by a multi-potent microRNA sponge.","Abstract":"The roles of oncogenic miRNAs are widely recognized in many cancers. Inhibition of single miRNA using antagomiR can efficiently knock-down a specific miRNA. However, the effect is transient and often results in subtle phenotype, as there are other miRNAs contribute to tumorigenesis. Here we report a multi-potent miRNA sponge inhibiting multiple miRNAs simultaneously. As a model system, we targeted miR-21, miR-155 and miR-221/222, known as oncogenic miRNAs in multiple tumors including breast and pancreatic cancers. To achieve efficient knockdown, we generated perfect and bulged-matched miRNA binding sites (MBS) and introduced multiple copies of MBS, ranging from one to five, in the multi-potent miRNA sponge. Luciferase reporter assay showed the multi-potent miRNA sponge efficiently inhibited 4 miRNAs in breast and pancreatic cancer cells. Furthermore, a stable and inducible version of the multi-potent miRNA sponge cell line showed the miRNA sponge efficiently reduces the level of 4 target miRNAs and increase target protein level of these oncogenic miRNAs. Finally, we showed the miRNA sponge sensitize cells to cancer drug and attenuate cell migratory activity. Altogether, our study demonstrates the multi-potent miRNA sponge is a useful tool to examine the functional impact of simultaneous inhibition of multiple miRNAs and proposes a therapeutic potential.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-221"}
{"PMID":28639885,"Year":2017,"Title":"MicroRNA-195 inhibits the proliferation and invasion of pancreatic cancer cells by targeting the fatty acid synthase/Wnt signaling pathway.","Abstract":"Emerging evidence suggests that microRNAs are critical regulators of cancer development and progression. MicroRNA-195 has been reported as a cancer-related microRNA in many human cancers. However, the role of microRNA-195 in pancreatic cancer remains largely unknown. Here, we show that microRNA-195 is downregulated in pancreatic cancer tissues and cell line. Also, we show that overexpression of microRNA-195 inhibits the proliferation and invasion of pancreatic cancer cells, whereas suppression of microRNA-195 promotes proliferation and invasion. We show that microRNA-195 directly targets the fatty acid synthase enzyme and negatively regulates the expression of fatty acid synthase. Also, we show that fatty acid synthase expression is inversely correlated with microRNA-195 expression in pancreatic cancer tissues. Moreover, our results show that microRNA-195 inhibits Wnt signaling in pancreatic cancer cells. By restoring fatty acid synthase expression, we were able to reverse the antitumor effects of microRNA-195 in pancreatic cancer cells. Taken together, our findings show that microRNA-195 inhibits pancreatic cancer cell proliferation and invasion by regulating the fatty acid synthase/Wnt signaling pathway, suggesting a tumor suppressive role for microRNA-195 in the development and progression of pancreatic cancer. Thus, inhibiting fatty acid synthase by microRNA-195 may serve as a novel therapeutic approach for the treatment of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-195"}
{"PMID":28677209,"Year":2017,"Title":"Downregulation of ULK1 by microRNA-372 inhibits the survival of human pancreatic adenocarcinoma cells.","Abstract":"Dysregulation of microRNA (miRNA) expression in various cancers and their role in cancer progression is well documented. The purpose of this study was to investigate the biological role of miR-372 in human pancreatic adenocarcinoma (HPAC). We collected 20 pairs of HPAC tissues and adjacent non-cancerous tissues to detect miR-372 expression levels. We transfected BXPC-3 and PANC-1 cells with miR-372 inhibitor/mimics to study their effect on cell proliferation, apoptosis, invasion, migration and autophagy. In addition, miR-372 mimics and a tumor protein UNC51-like kinase 1 (ULK1) siRNA were co-transfected into BXPC-3 and PANC-1 cells to explore the mechanism of miR-372 and ULK1 on HPAC tumorigenesis. We found that the expression of miR-372 was markedly downregulated in HPAC cells compared to adjacent normal tissues. Furthermore, functional assays showed that miR-372 inhibited cell proliferation, invasion, migration and autophagy in BXPC-3 and PANC-1 cells. An inverse correlation between miR-372 expression and ULK1 expression was observed in HPAC tissues. Downregulation of ULK1 inhibited the overexpression effects of miR-372, and upregulation of ULK1 reversed the effects of overexpressed miR-372. Finally, we found that silencing ULK1 or inhibiting autophagy partly rescued the effects of miR-372 knockdown in HPAC cells, which may explain the influence of miR-372/ULK1 in HPAC development. Taken together, these results revealed a significant role of the miR-372/ULK1 axis in suppressing HPAC cell proliferation, migration, invasion and autophagy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-372"}
{"PMID":26828016,"Year":2016,"Title":"MicroRNA-101-3p reverses gemcitabine resistance by inhibition of ribonucleotide reductase M1 in pancreatic cancer.","Abstract":"Pancreatic ductal adenocarcinoma (PDA) is among the most lethal malignancies and resistance to chemotherapy prevents the therapeutic outcome. MicroRNAs provide a novel therapeutic strategy. Here, the established and primary human PDA cell lines PANC-1, AsPC-1, MIA-PaCa2, AsanPaCa, BxPC-3 and three gemcitabine-resistant subclones were examined. A gene expression profiling revealed that the ribonucleotide reductase M1 (RRM1) was upregulated in gemcitabine-resistant cells, which was confirmed by qRT-PCR, Western blot analysis and immunostaining. Inhibition of RRM1 by lipotransfection of siRNA reduced its expression and reversed gemcitabine resistance. The expression of RRM1 correlated to gemcitabine resistance in vitro and was higher in malignant patient pancreas tissue compared to non-malignant pancreas tissue. By microRNA expression profiling, we identified microRNA-101-3p as top-downregulated candidate. Lipotransfection of microRNA-101-3p mimics inhibited the expression of RRM1, reduced the luciferase activity of its 3'UTR and sensitized for gemcitabine-induced cytotoxicity. These results underline the relevance of microRNA-101-3p-driven regulation of RRM1 in drug resistance and suggest the co-delivery of microRNA-101-3p and gemcitabine for more effective therapy outcome.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-101"}
{"PMID":27573701,"Year":2016,"Title":"miR1246 and miR4644 in salivary exosome as potential biomarkers for pancreatobiliary tract cancer.","Abstract":"Pancreatobiliary tract cancer is a highly fatal cancer. Detection of pancreatobiliary tract cancer is difficult because it lacks typical clinical symptoms and because of its anatomical location. Biomarker discovery is therefore important to detect pancreatobiliary tract cancer in its early stage. A study demonstrated that expression levels of miR1246, miR3976, miR4306, and miR4644 in serum exosomes were higher in pancreatic cancer patients than these levels in healthy control participants. Supposing that microRNA (miRNA) expression profiles in saliva are similar to those in serum, four miRNAs (miR1246, miR3976, miR4306, and miR4644) in salivary exosomes may also be useful for detection of pancreatobiliary tract cancer. In this study, it was examined whether these miRNAs could be used as biomarkers for pancreatobiliary tract cancer. Twelve pancreatobiliary tract cancer patients and 13 healthy control participants were analyzed as a cancer and a control group, respectively. Unstimulated whole saliva was collected, salivary exosomes were isolated, and total RNA was extracted. Using quantitative realtime PCR (RTqPCR), the relative expression ratios of miR1246 and miR4644 were significantly higher in the cancer group than these ratios in the control group. Receiver operating characteristic (ROC) curves were constructed to analyze the discrimination power of these miRNAs. For miR1246, the results yielded an area under the curve (AUC) of 0.814 (P=0.008). For miR4644, the results yielded an AUC of 0.763 (P=0.026). For the combination of miR1246 and miR4644, the results yielded an increased AUC of 0.833 (P=0.005). This pilot study suggests that miR1246 and miR4644 in salivary exosomes could be candidate biomarkers for pancreatobiliary tract cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-4306"}
{"PMID":31031600,"Year":2019,"Title":"Silencing MicroRNA-134 Alleviates Hippocampal Damage and Occurrence of Spontaneous Seizures After Intraventricular Kainic Acid-Induced Status Epilepticus in Rats.","Abstract":"Epilepsy is a disorder of abnormal brain activity typified by spontaneous and recurrent seizures. MicroRNAs (miRNAs) are short non-coding RNAs, critical for the post-transcriptional regulation of gene expression. MiRNA dysregulation has previously been implicated in the induction of epilepsy. In this study, we examined the effect of silencing miR-134 against status epilepticus (SE). Our results showed that level of miR-134 was significantly up-regulated in rat brain after Kainic acid (KA)-induced SE. TUNEL staining showed that silencing miR-134 alleviated seizure-induced neuronal apoptosis in the CA3 subfield of the hippocampus. Western blot showed that a miR-134 antagonist suppressed lesion-induced endoplasmic reticulum (ER) stress and apoptosis related expression of CHOP, Bim and Cytochrome C, while facilitated the expression of CREB at 24 h post KA-induced lesion in the hippocampus. Consistently, silencing miR-134 significantly diminished loss of CA3 pyramidal neurons using Nissl staining as well as reducing aberrant mossy fiber sprouting (MFS) in a rat epileptic model. In addition, the results of EEG and behavior analyses showed seizures were alleviated by miR-134 antagonist in our experimental models. These results suggest that silencing miR-134 modulates the epileptic phenotype by upregulating its target gene, CREB. This in turn attenuates oxidative and ER stress, inhibits apoptosis, and decreases MFS long term. This indicates that silencing miR-134 might be a promising intervention for the treatment of epilepsy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-134"}
{"PMID":22851141,"Year":2012,"Title":"Prognostic microRNAs in cancer tissue from patients operated for pancreatic cancer--five microRNAs in a prognostic index.","Abstract":"BACKGROUND: The aim of the present study was to identify a panel of microRNAs (miRNAs) that can predict overall survival (OS) in non micro-dissected cancer tissues from patients operated for pancreatic cancer (PC). METHODS: MiRNAs were purified from formalin-fixed paraffin embedded (FFPE) cancer tissue from 225 patients operated for PC. Only a few of those patients received adjuvant chemotherapy. Expressions of miRNAs were determined with the TaqMan MicroRNA Array v2.0. Two statistical methods, univariate selection and the Lasso (Least Absolute Shrinkage and Selection Operator) method, were applied in conjunction with the Cox proportional hazard model to relate miRNAs to OS. RESULTS: High expression of miR-212 and miR-675 and low expression of miR-148a, miR-187, and let-7g predicted short OS independent of age, gender, calendar year of operation, KRAS mutation status, tumor stage, American Society of Anesthesiologists (ASA) score, localization (not miR-148a), and differentiation of tumor. A prognostic index (PI) based on these five miRNAs was calculated for each patient. The median survival was 1.09 years (Confidence Interval [CI] 0.98-1.43) for PI > median PI compared to 2.23 years (CI 1.84-4.36) for PI < median. MiR-212, miR-675, miR-187, miR-205, miR-944, miR-431, miR-194, miR-148a, and miR-769-5p showed the strongest prediction ability by the Lasso method. Thus miR-212, miR-675, miR-187, and miR-148a were predictors for OS in both statistical methods. CONCLUSIONS: The combination of five miRNAs expression in non micro-dissected FFPE PC tissue can identify patients with short OS after radical surgery. The results are independent of chemotherapy treatment. Patients with a prognostic index > median had a very short median OS of only 1 year.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-675"}
{"PMID":25884472,"Year":2015,"Title":"Long noncoding RNA CCAT1 promotes hepatocellular carcinoma progression by functioning as let-7 sponge.","Abstract":"BACKGROUND: Long noncoding RNAs (lncRNAs) have been identified as having functional roles in cancer biology and are deregulated in many cancers. The present study aimed to determine the expression, roles and functional mechanisms of a long noncoding RNA CCAT1 in the progression of hepatocellular carcinoma (HCC). METHODS: CCAT1 expression levels in 66 pairs of HCC tissues and pair-matched noncancerous hepatic tissues were tested by real-time PCR. The effects of CCAT1 on HCC cells proliferation and migration were assessed using in vitro cell proliferation and migration assays. A computational screen of microRNAs (miRNAs) target sites in CCAT1 was conducted to search for specific miRNAs binding to CCAT1. The specific binding between CCAT1 and miRNAs was confirmed by RNA immunoprecipitation assay combined with luciferase reporter assay. RESULTS: CCAT1 levels are markedly increased in HCC tissues compared with pair-matched noncancerous hepatic tissues. Up-regulation of CCAT1 is correlated with tumor size, microvascular invasion, AFP and poor prognosis. CCAT1 promotes the proliferation and migration of HCC cells. CCAT1 functions as a molecular sponge for let-7, antagonizes its functions, and leads to the de-repression of its endogenous targets HMGA2 and c-Myc. The effect of CCAT1 on HCC cell proliferation and migration is dependent upon its competitively binding to let-7. CONCLUSIONS: These data suggest that CCAT1 plays a pivotal role in HCC progression via functioning as let-7 sponge, and implicate the potential application of CCAT1 for the prognosis and treatment of HCC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"let-7"}
{"PMID":20356498,"Year":2010,"Title":"[Effect of anti-cancer drugs on the expression of BIC/miR-155 in human pancreatic cancer PANC-1 cells].","Abstract":"OBJECTIVE: To investigate the effect of anti-cancer drugs on the expression of B-cell integration cluster (BIC) RNA/miRNA-155 in human pancreatic cancer PANC-1 cells. METHODS: PANC-1 cells were treated with different concentrations of anti-cancer drugs. Total RNA of the treated cells were harvested and the expression levels of BIC RNA and mature miR-155 were quantified by using Taqman FAM/MGB probes on a real-time PCR system. Relative quantification was carried out using the DeltaDeltaCt method. A PI3K-related kinases inhibitor was used to determine whether these kinases were involved in the regulation of BIC RNA. RESULTS: The expression of BIC RNA was strongly induced by anti-cancer drugs. When PANC-1 cells were treated by gemcitabine with concentrations of 1.0, 2.5, 5.0, 10.0 mg/L for 48 h and 72 h, the level of BIC RNA (48 h: 37.1 +/- 4.1, 29.0 +/- 5.7, 21.0 +/- 7.6, 40.4 +/- 9.0, 72 h: 27.7 +/- 3.1, 43.1 +/- 1.2, 31.8 +/- 5.4, 23.1 +/- 1.4) were significantly higher than that of the control (48 h: 1.6 +/- 1.1, 72 h: 1.0 +/- 0.1, all P < 0.05). 5-FU (10 mg/L, 48 h) and bleomycin (100 mg/L, 48 h) also induced BIC RNA up-regulation (5.2 +/- 1.1 vs 1.7 +/- 0.7, 11.5 +/- 0.7 vs 1.7 +/- 0.7, both P < 0.05). When PANC-1 cells treated with 1.0, 2.5, 5.0, 10.0 mg/L gemcitabine for 72 h, the level of miR-155 (2.21 +/- 0.40, 1.86 +/- 0.03, 2.47 +/- 0.04, 3.24 +/- 0.05) also higher than that of the control (1.11 +/- 0.09, P < 0.05), while no change was observed when the cells only treated for 48 h. Further study showed gemcitabine-induced BIC RNA up-regulation was inhibited by wortmannin, a specific PI3K inhibitor, the expression levels of BIC RNA of 1 micromol/L wortmannin + 5 mg/L gemcitabine group and 10 micromol/L wortmannin + 5 mg/L gemcitabine group were 5.34 +/- 1.11 and 1.26 +/- 0.07, lower than that of 5 mg/L gemcitabine group (11.82 +/- 3.11, P < 0.05). CONCLUSIONS: BIC RNA is strongly induced by anti-cancer drugs in PANC-1 cells and the levels of miR-155 also slightly increase. PI3K pathway is involved in gemcitabine-induced BIC RNA up-regulation.","Language":"chi","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-155"}
{"PMID":25706130,"Year":2015,"Title":"MicroRNA markers for the diagnosis of pancreatic and biliary-tract cancers.","Abstract":"It is difficult to detect pancreatic cancer or biliary-tract cancer at an early stage using current diagnostic technology. Utilizing microRNA (miRNA) markers that are stably present in peripheral blood, we aimed to identify pancreatic and biliary-tract cancers in patients. With \"3D-Gene\", a highly sensitive microarray, we examined comprehensive miRNA expression profiles in 571 serum samples obtained from healthy patients, patients with pancreatic, biliary-tract, or other digestive cancers, and patients with non-malignant abnormalities in the pancreas or biliary tract. The samples were randomly divided into training and test cohorts, and candidate miRNA markers were independently evaluated. We found 81 miRNAs for pancreatic cancer and 66 miRNAs for biliary-tract cancer that showed statistically different expression compared with healthy controls. Among those markers, 55 miRNAs were common in both the pancreatic and biliary-tract cancer samples. The previously reported miR-125a-3p was one of the common markers; however, it was also expressed in other types of digestive-tract cancers, suggesting that it is not specific to cancer types. In order to discriminate the pancreato-biliary cancers from all other clinical conditions including the healthy controls, non-malignant abnormalities, and other types of cancers, we developed a diagnostic index using expression profiles of the 10 most significant miRNAs. A combination of eight miRNAs (miR-6075, miR-4294, miR-6880-5p, miR-6799-5p, miR-125a-3p, miR-4530, miR-6836-3p, and miR-4476) achieved a sensitivity, specificity, accuracy and AUC of 80.3%, 97.6%, 91.6% and 0.953, respectively. In contrast, CA19-9 and CEA gave sensitivities of 65.6% and 40.0%, specificities of 92.9% and 88.6%, and accuracies of 82.1% and 71.8%, respectively, in the same test cohort. This diagnostic index identified 18/21 operable pancreatic cancers and 38/48 operable biliary-tract cancers in the entire cohort. Our results suggest that the assessment of these miRNA markers is clinically valuable to identify patients with pancreato-biliary cancers who could benefit from surgical intervention.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-125"}
{"PMID":25087086,"Year":2014,"Title":"Bioinformatics method to predict two regulation mechanism: TF-miRNA-mRNA and lncRNA-miRNA-mRNA in pancreatic cancer.","Abstract":"Altered expressions of microRNAs (miRNAs) are reported in pancreatic cancer and associate with cancer pathogenesis, apoptosis, and cell growth, thereby functioning as either tumor suppressors or oncogenes. However, the majority of studies focus on defining the regulatory functions of miRNAs, whereas few investigations are directed toward assessing how the miRNA themselves are transcriptionally regulated. In this study, integration of published multi-level expression data and bioinformatics computational approach was used to predict two regulation mechanisms: transcription factors (TF)-miRNA-mRNA regulation and long non-coding RNA(lncRNA)-miRNA-mRNA regulation. To identify differentially expressed mRNAs, miRNAs, and lncRNAs, we integrated microarray expression data in pancreatic cancer tissues and normal tissues. Combination of differentially expressed mRNAs and miRNAs with miRNA-mRNA interactions based on crosslinking and immunoprecipitation followed by high-throughput sequencing (CLIP-Seq) data from StarBas, we constructed miRNA-mRNA regulatory network. Then we constructed two regulatory networks including TF-miRNA-mRNA and lncRNA-miRNA-mRNA based on chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from ChIPBase and CLIP-Seq data. A total of 4385 mRNAs, 500 miRNAs, and 21 lncRNAs were differentially expressed, of which, 18 mRNAs and 54 miRNAs are with high confidence. In miRNA-mRNA regulatory network, interrelated miRNAs target 1701 differentially regulated mRNAs. By constructing regulatory network, 19miRNAs including hsa-miR-137, hsa-miR-206, hsa-miR-429, hsa-miR-320d, and hsa-miR-320c are predicted to participate in lncRNA-miRNA-mRNA regulation. Furthermore, 8 miRNAs including hsa-mir-137, hsa-mir-206, hsa-mir-429, hsa-mir-375, hsa-mir-326, hsa-mir-217, hsa-mir-301b, and hsa-mir-184 are predicted to participate in TF-miRNA-mRNA regulation. In an integrated data analysis, we reveal large-scale effects of interrelated miRNAs and provide a model for predicting the mechanism of miRNAs disorder. Our study provides a new insight into understanding the transcriptional regulation of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-429"}
{"PMID":28122349,"Year":2017,"Title":"The prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma.","Abstract":"Different clinical presentations and prognoses have been implied between pancreatic head and body/tail cancers. We aimed to identify the prognostic relevance of primary tumor location in patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). Thirty-two pairs of patients with strictly matched early stage (II) pancreatic head and body/tail cancers were enrolled. The molecular feature of the two subtypes of PDAC was assessed on the level of miRNA expression. Out of the 64 patients, 34 (53.1%) had tumor recurrence after radical resection during the follow-up period (2.3 +/- 0.8 years). Both overall and tumor-free survival were significantly higher in the patients with pancreatic body/tail cancer compared with those with pancreatic head cancer. Patient age and tumor location were the independent prognostic factors for tumor recurrence. A remarkably lower expression of miR-501-3p and higher expression of miR-375 were found and were further verified in pancreatic body/tail cancer tissues compared with pancreatic head cancer tissues. The low expression of miR-501-3p was significantly associated with a low risk of tumor recurrence. Both, subcutaneous and orthotopic PDAC mouse models presented highly invasive tumor phenotypes upon up-regulated miR-501-3p expression. An in vitro study showed that miR-501-3p promoted the invasiveness of PDAC cells possibly via suppressing E-cadherin. In summary, at resectable early stage, pancreatic body/tail cancer presents a less malignant phenotype associated with deregulation of miR-501-3p compared with pancreatic head cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-501"}
{"PMID":21285251,"Year":2011,"Title":"DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism.","Abstract":"Pancreatic cancer is an exceptionally aggressive disease in great need of more effective therapeutic options. Epithelial-mesenchymal transition (EMT) plays a key role in cancer invasion and metastasis, and there is a gain of stem cell properties during EMT. Here we report increased expression of the putative pancreatic stem cell marker DCAMKL-1 in an established KRAS transgenic mouse model of pancreatic cancer and in human pancreatic adenocarcinoma. Colocalization of DCAMKL-1 with vimentin, a marker of mesenchymal lineage, along with 14-3-3 sigma was observed within premalignant PanIN lesions that arise in the mouse model. siRNA-mediated knockdown of DCAMKL-1 in human pancreatic cancer cells induced microRNA miR-200a, an EMT inhibitor, along with downregulation of EMT-associated transcription factors ZEB1, ZEB2, Snail, Slug, and Twist. Furthermore, DCAMKL-1 knockdown resulted in downregulation of c-Myc and KRAS through a let-7a microRNA-dependent mechanism, and downregulation of Notch-1 through a miR-144 microRNA-dependent mechanism. These findings illustrate direct regulatory links between DCAMKL-1, microRNAs, and EMT in pancreatic cancer. Moreover, they demonstrate a functional role for DCAMKL-1 in pancreatic cancer. Together, our results rationalize DCAMKL-1 as a therapeutic target for eradicating pancreatic cancers.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"let-7"}
{"PMID":26348713,"Year":2015,"Title":"Tissue-Specific Molecular Biomarker Signatures of Type 2 Diabetes: An Integrative Analysis of Transcriptomics and Protein-Protein Interaction Data.","Abstract":"Type 2 diabetes mellitus is a major global public health burden. A complex metabolic disease, type 2 diabetes affects multiple different tissues, demanding a \"systems medicine\" approach to biomarker and novel diagnostic discovery, not to mention data integration across omics-es. In the present study, transcriptomics data from different tissues including beta-cells, pancreatic islets, arterial tissue, peripheral blood mononuclear cells, liver, and skeletal muscle of 228 samples were integrated with protein-protein interaction data and genome scale metabolic models to unravel the molecular and tissue-specific biomarker signatures of type 2 diabetes mellitus. Classifying differentially expressed genes, reconstruction and topological analysis of active protein-protein interaction subnetworks indicated that genomic reprogramming depends on the type of tissue, whereas there are common signatures at different levels. Among all tissue and cell types, Mannosidase Alpha Class 1A Member 2 was the common signature at genome level, and activation-ppara reaction, which stimulates a nuclear receptor protein, was found out as the mutual reporter at metabolic level. Moreover, miR-335 and miR-16-5p came into prominence in regulation of transcription at different tissues. On the other hand, distinct signatures were observed for different tissues at the metabolome level. Various coenzyme-A derivatives were significantly enriched metabolites in pancreatic islets, whereas skeletal muscle was enriched for cholesterol, malate, L-carnitine, and several amino acids. Results have showed utmost importance concerning relations between T2D and cancer, blood coagulation, neurodegenerative diseases, and specific metabolic and signaling pathways.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-335"}
{"PMID":26214431,"Year":2015,"Title":"Propofol suppresses proliferation and invasion of pancreatic cancer cells by upregulating microRNA-133a expression.","Abstract":"Propofol is a commonly used intravenous anesthetic. We evaluated its effects on the behavior of human pancreatic cancer cells and the underlying molecular mechanisms. The effects of propofol on Panc-1 cell proliferation, apoptosis, and invasion were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, caspase-3 activity measurement, and Matrigel invasion assay. Quantitative polymerase chain reaction (qPCR) was used to assess microRNA-133a (miR-133a) expression. Anti-miR-133a was transfected into Panc-1 cells to assess the role of miR-133a in propofol-induced antitumor activity. Propofol significantly inhibited Panc-1 cell proliferation and invasion, and promoted apoptosis. Propofol also efficiently elevated miR-133a expression. Moreover, transfection of anti-miR-133a reversed the effects of propofol on the biological behavior of Panc-1 cells. Propofol can effectively inhibit proliferation and invasion, and induce apoptosis of pancreatic cancer cells, at least partly through the upregulation of miR-133a expression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-133"}
{"PMID":30306823,"Year":2018,"Title":"MicroRNA therapeutics: design of single-stranded miR-216b mimics to target KRAS in pancreatic cancer cells.","Abstract":"Datasets reporting microRNA expression profiles in normal and cancer cells show that miR-216b is aberrantly downregulated in pancreatic ductal adenocarcinoma (PDAC). We found that KRAS, whose mutant G12D allele drives the pathogenesis of PDAC, is a target of miR-216b. To suppress oncogenic KRAS in PDAC cells, we designed single-stranded (ss) miR-216b mimics with unlocked nucleic acid (UNA) modifications to enhance their nuclease resistance. We prepared variants of ss-miR-216b mimics with and without a 5' phosphate group. Both variants strongly suppressed oncogenic KRAS in PDAC cells and inhibited colony formation in pancreatic cancer cells. We observed that the designed ss-miR-216b mimics engaged AGO2 to promote the silencing of KRAS. We also tested a new delivery strategy based on the use of palmityl-oleyl-phosphatidylcholine (POPC) liposomes functionalized with ss-miR-216b conjugated with two palmityl chains and a lipid-modified cell penetrating peptide (TAT). These versatile nanoparticles suppressed oncogenic KRAS in PDAC cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-216"}
{"PMID":28987387,"Year":2018,"Title":"MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes.","Abstract":"The members of the miR-17-92 cluster are upregulated in various cancers and function as a cluster of oncogenic miRNA. Our study characterized a new function of miR-17-5p, a member of the miR-17-92 cluster, in regulating cell proliferation in pancreatic cancer. Our results indicate that miR-17-5p was up-regulated in pancreatic adenocarcinoma and directly targeted the retinoblastoma-like protein 2 (RBL2), a tumor suppressor belonging to the Rb family. High levels of miR-17-5p and low levels of RBL2 were associated with poor prognosis. RBL2 interacted with the transcription factor E2F4 and bound to the promoter regions of the E2F target genes. Disruption of the RBL2/E2F4 complex by miR-17-5p overexpression shifted the activity of E2F from gene repressing to gene activating, which induced cell cycle entry and proliferation. These results suggest that miR-17-5p promoted proliferation in pancreatic ductal adenocarcinoma cells (PDAC), and altered cell cycle profiles in vivo and in vitro, by disrupting the RBL2/E2F4-associated gene repressing complexes via direct targeting of RBL2. The new regulatory network, involving miR-17-5p and RBL2, emerges as a new target of PDAC treatment.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-17"}
{"PMID":28373289,"Year":2017,"Title":"miR-202 Diminishes TGFbeta Receptors and Attenuates TGFbeta1-Induced EMT in Pancreatic Cancer.","Abstract":"Previous studies in our laboratory identified that 3-deazaneplanocin A (DZNep), a carbocyclic adenosine analog and histone methyl transferase inhibitor, suppresses TGFbeta-induced epithelial-to-mesenchymal (EMT) characteristics. In addition, DZNep epigenetically reprograms miRNAs to regulate endogenous TGFbeta1 levels via miR-663/4787-mediated RNA interference (Mol Cancer Res. 2016 Sep 13. pii: molcanres.0083.2016) (1). Although DZNep also attenuates exogenous TGFbeta-induced EMT response, the mechanism of this inhibition was unclear. Here, DZNep induced miR-202-5p to target both TGFbeta receptors, TGFBR1 and TGFBR2, for RNA interference and thereby contributes to the suppression of exogenous TGFbeta-induced EMT in pancreatic cancer cells. Lentiviral overexpression of miR-202 significantly reduced the protein levels of both TGFbeta receptors and suppressed TGFbeta signaling and EMT phenotypic characteristics of cultured parenchymal pancreatic cancer cells. Consistently, transfection of anti-miRNAs against miR-202-5p resulted in increased TGFBR1 and TGFBR2 protein expressions and induced EMT characteristics in these cells. In stellate pancreatic cells, miR-202 overexpression slowed growth as well as reduced stromal extracellular membrane matrix protein expression. In orthotopic pancreatic cancer mouse models, both immunodeficient and immunocompetent, miR-202 reduced tumor burden and metastasis. Together, these findings demonstrate an alternative mechanism of DZNep in suppressing TGFbeta signaling at the receptor level and uncover the EMT-suppressing role of miR-202 in pancreatic cancer.Implications: These findings support the possibility of combining small molecule-based (e.g., DZNep analogs) or large molecule-based (e.g., miRNAs) epigenetic modifiers with conventional nucleoside analogs (e.g., gemcitabine, capecitabine) to improve the antimetastatic potential of current pancreatic cancer therapy. Mol Cancer Res; 15(8); 1029-39. (c)2017 AACR.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-202"}
{"PMID":26747707,"Year":2016,"Title":"Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1.","Abstract":"UNLABELLED: Activating KRAS mutations are nearly ubiquitous in pancreatic cancer occurring in more than 95% of clinical cases. miRNAs are small noncoding RNAs that regulate gene expression by binding sequences within the 3'UTRs of target mRNAs. An integral role for miRNAs in cancer pathogenesis is well established; however, the role of miRNAs in KRAS-mediated tumorigenesis is poorly characterized. Here it is demonstrated that expression of miR-31 is coupled to the expression of oncogenic KRAS and activity of the MAPK pathway. miR-31 is highly expressed in patient-derived xenografts and a panel of pancreatic and colorectal cancer cells harboring activating KRAS mutations. The miR-31 host gene is a large noncoding RNA that correlates with miR-31 expression and enabled identification of the putative miR-31 promoter. Using luciferase reporters, a minimal RAS-responsive miR-31 promoter was found to drive robust luciferase activity dependent on expression of mutant KRAS and the transcription factor ELK1. Furthermore, ELK1 interacts directly with the endogenous miR-31 promoter in a MAPK-dependent manner. Expression of enforced miR-31 significantly enhanced invasion and migration of multiple pancreatic cancer cells resulting from the activation of RhoA through regulation of the miR-31 target gene RASA1. Importantly, acute knockdown of RASA1 phenocopied enforced miR-31 expression on the migratory behavior of pancreatic cancer cells through increased RhoA activation. IMPLICATIONS: Oncogenic KRAS can activate Rho through the miR-31-mediated regulation of RASA1 indicating miR-31 acts as a KRAS effector to modulate invasion and migration in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-31"}
{"PMID":28693279,"Year":2017,"Title":"MicroRNA-215 acts as a tumor suppressor in breast cancer by targeting AKT serine/threonine kinase 1.","Abstract":"There are accumulating reports that microRNAs are dysregulated in a number of human cancer types, and that they may function as tumor suppressors or oncogenes in tumorigenesis and tumor development. microRNA-215 (miR-215) has been identified as a tumor suppressor in epithelial ovarian, pancreatic, non-small cell lung and colon cancer, whereas it may act as an oncogene in gastric and cervical cancer. The role of miR-215 in breast cancer carcinogenesis and progression has yet to be elucidated. In the present study, the expression level of miR-215 was determined in breast cancer tissues and cell lines using the reverse transcription-quantitative polymerase chain reaction. The effects of miR-215 overexpression on proliferation and the invasive capacity of breast cancer cells were assessed using MTT and cell invasion assays. The results revealed that miR-215 was significantly downregulated in breast cancer tissues and cell lines. Restoration of miR-215 expression inhibited the proliferation and invasion of breast cancer cells. The underlying molecular mechanism for the suppression of proliferation and invasion by miR-215 was investigated. AKT serine/threonine kinase 1 (AKT1) was validated as a novel direct target of miR-215, and the effect of AKT1 small interfering RNA mimicked the effect of miR-215 overexpression in breast cancer cells. These results indicated that miR-215 acted as a tumor suppressor, and that its downregulation in tumor tissues may contribute to the carcinogenesis and progression of breast cancer, indicating that miR-215 may be a novel therapeutic target for the treatment of breast cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-215"}
{"PMID":29962816,"Year":2018,"Title":"Novel serum microRNAs panel on the diagnostic and prognostic implications of hepatocellular carcinoma.","Abstract":"AIM: To determine a panel of serum microRNAs (miRNAs) that could be used as novel biomarkers for diagnosis of hepatocellular carcinoma (HCC). METHODS: We initially screened 9 out of 754 serum miRNAs by TaqMan Low Density Array in two pooled samples respectively from 35 HCC and 35 normal controls, and then validated individually by RT-qPCR in another 114 patients and 114 controls arranged in two phases. The changes of the selected miRNAs after operation and their prognostic value were examined. RESULTS: miR-375, miR-10a, miR-122 and miR-423 were found to be significantly higher in HCC than in controls (P < 0.0001), and the area under the receiver-operating-characteristic curve for the 4-miRNA panel was 0.995 (95%CI: 0.985-1). All the four miRNAs were significantly reduced after surgical removal of the tumors (P < 0.0001), while still higher than normal controls (at least P < 0.05). CONCLUSION: The four serum miRNAs (miR-375, miR-10a, miR-122 and miR-423) could potentially serve as novel biomarkers for the diagnostic and prognostic of HCC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-122"}
{"PMID":20638779,"Year":2010,"Title":"miR-27a regulates the growth, colony formation and migration of pancreatic cancer cells by targeting Sprouty2.","Abstract":"MicroRNAs are short regulatory RNAs. A growing body of data implicates altered miRNA participate in the development of cancers and miR-27a is abnormally upregulated in several types of cancers identified as an oncogene. Although overexpressed in pancreatic adenocarcinoma, the oncogenic role of miR-27a has not yet been reported. In this study, we showed that inhibition of miR-27a suppressed the growth, colony formation and migration of pancreatic cancer cells. By using a reporter-screening assay, we discovered that the 3'UTR of Sprouty2 (Spry2) carried a putative miR-27a binding site. Furthermore, the Spry2 protein, which has a low expression level in pancreatic adenocarcinoma, was upregulated by transfection with a miR-27a inhibitor. The data reported here are the first to indicate that miR-27a plays an oncogenic role by targeting Spry2 and modulating the malignant, biological behavior of pancreatic cancer cells. This suggests the potential for miR-27a to be used as a target in the diagnosis and treatment of pancreatic adenocarcinoma.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-27"}
{"PMID":27840954,"Year":2016,"Title":"Identfication of key miRNAs in pancreatitis using bioinformatics analysis of microarray data.","Abstract":"Pancreatitis is a type of inflammation in the pancreas, which frequently occurs due to alcohol and gallstones. The present study aimed to identify pancreatitisassociated microRNAs (miRNAs) by analyzing the microarray of GSE24279. GSE24279 was downloaded from the Gene Expression Omnibus, composed of a collective of 27 pancreatitis and 22 normal control samples. The differentially expressed miRNAs (DEmiRNAs) in pancreatitis samples were screened using the Limma package in Bioconductor. Subsequently, target genes of the DEmiRNAs were predicted using the miRecords and miRWalk databases. Their potential functions were analyzed by functional and pathway enrichment analysis using the Database for Annotation, Visualization and Integrated Discovery online tool. Finally, pancreatitisassociated genes among the target genes identified were searched using the Comparative Toxicogenomics Database, and a regulatory network of pancreatitisassociated genes and their target miRNAs were constructed using Cytoscape software. A total 14 upregulated and 39 downregulated miRNAs were identified in pancreatitis samples compared with control samples and 290 target genes of DEmiRNAs were determined. Cyclin D1 (CCND1), vakt murine thymoma viral oncogene homolog 2 (AKT2), cyclindependent kinase 6 (CDK6) and SMAD family member 2 (SMAD2) were involved in the pathway of pancreatic cancer. Among the target genes, 279 genes were pancreatitisassociated genes, which in turn were targeted by 37 miRNAs in the regulatory network. HsamiR15a, hsamiR16, hsamiR155, hsamiR375 and hsamiR429 in particular may be involved in pancreatitis by targeting genes in the regulatory network, including hsamiR15a-->CCND1, hsamiR16-->CCND1, hsamiR155-->CCND1/SMAD2, hsamiR375-->AKT2/CDK6 and hsamiR429-->CCND1. The above miRNAs and their targets may contribute to the pathogenesis of pancreatitis; therefore, they may be potential therapeutic targets.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-429"}
{"PMID":26498682,"Year":2015,"Title":"MiR-652 inhibits acidic microenvironment-induced epithelial-mesenchymal transition of pancreatic cancer cells by targeting ZEB1.","Abstract":"Recent evidences suggest that the acidic microenvironment might facilitate epithelial mesenchymal transition (EMT) of tumor cells, while the effects of acidity on EMT of pancreatic cancer (PC) remain undefined. The present study demonstrated that acidity suppressed miR-652 expression, which further promoted EMT process by absenting inhibition on the transcriptional factor ZEB1 expression. At first, we found that acidity remarkably enhanced invasion ability of PC cells accompanying with increased mesenchymal and decreased epithelial markers. Meanwhile, miRNAs-microarray showed that miR-652, the potential regulator of ZEB1, was distinctly decreased in acidity-treated PC cells. Furthermore, restoration of miR-652 reversed acidity-induced EMT by inhibiting ZEB1 expression, while miR-652 inhibitor induced EMT in normal PC cells through promoting ZEB1 expression. Nevertheless, knockdown of ZEB1 significantly suppressed acidity-induced EMT in PC cells, but ZEB1 overexpression rescued the EMT which was inhibited by miR-652 overexpression. The in vivo results showed that the tumor growth and liver metastasis were remarkably retarded by both miR-652 overexpression and ZEB1 knockdown. The clinical samples further revealed that miR-652 was decreased in PC tissues and antagonistically correlated with ZEB1 expression, associating with late tumor stage, lymphatic invasion and metastasis. In conclusion, our study indicated a novel acidity/miR-652/ZEB1/EMT axis in the tumorigenesis of PC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-652"}
{"PMID":30537722,"Year":2019,"Title":"Expression Levels of microRNAs miR-93 and miR-200a in Pancreatic Adenocarcinoma with Special Reference to Differentiation and Relapse-Free Survival.","Abstract":"OBJECTIVES: Protein levels of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) and its inhibitor Kelch-like ECH-associated protein 1 (Keap1) have been proposed as prognostic factors in pancreatic ductal adenocarcinomas (PDACs). These cellular redox-state-regulating enzymes are targeted by several microRNAs, including miR-93 and miR-200a. METHODS: We assessed mRNA levels of Nrf2 and Keap1 and tissue expression of miR-93 and miR-200a in 51 patients with surgically treated PDAC. Expression levels were separately measured in malignant cells and adjacent benign cells. RESULTS: Keap1 and Nrf2 mRNA expression levels in cancer cells were lower than in adjacent benign tissue (Wilcoxon's test; p = 0.0015 and p = 0.000032, respectively). Conversely, miR-93 expression was higher in cancer cells than in adjacent benign tissue (p = 0.00082). Low levels of miR-93 and miR-200a in cancer cells were associated with poorer differentiation (p = 0.004 and p = 0.002, respectively). In univariate survival analysis, benign-tissue levels of miR-200a above the median predicted better relapse-free survival (RFS) (p = 0.045). CONCLUSIONS: High miR-93 and miR-200a levels in cancer cells of PDAC were associated with better differentiation, and miR-200a expression in benign tissue with excellent RFS. Keap1 and Nrf2 mRNA levels showed prominent down-regulation in cancerous versus benign tissue, but they were not associated with disease aggressiveness or outcome.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-93"}
{"PMID":29800682,"Year":2018,"Title":"Pancreatic cancer-derived exosomes suppress the production of GIP and GLP-1 from STC-1cells in vitro by down-regulating the PCSK1/3.","Abstract":"One hallmark of pancreatic cancer (PC) is the high prevalence of pancreatic cancer-associated diabetes mellitus (PC-DM), but the mechanisms remain to be elucidated. Patients with PC who are diagnosed with new-onset diabetes/prediabetes have recently been shown to display significantly lower levels of glucose-dependent insulinotropic peptide (GIP) secreted mainly by enteroendocrine cells. We hypothesized that PC-derived exosomes are responsible for the decreased levels of incretins in patients with PC-DM. In this study, exosomes were successfully isolated from PANC-1, MIA PaCa-2 and SW620cells and characterized. Only the exosomes from MIA PaCa-2cells (Exo-Mia) reduce the production of GIP and glucagon-like peptide-1 (GLP-1) from STC-1cells in vitro in a concentration- and time-dependent manner. Moreover, Exo-Mia increased the levels of the Gip and proglucagon mRNAs and decreased the expression of proprotein convertase subtilisin/kexin type 1/3 (PCSK1/3), which is responsible for the post-translational processing of Gip and proglucagon. Furthermore, differentially expressed exosomal miRNAs (miR-6796-3p, miR-6763-5p, miR-4750-3p and miR-197-3p) were identified and considered to be responsible for the inhibitory effects on GIP and GLP-1 production. To further determine the approach of cancer-derived exosomes reaching enteroendocrine cells, we analyzed the uptake and distribution of exosomes in animal model. It was observed that exosomes infused into the intestinal cavity were more easily internalized by the intestinal epithelium than exosomes injected into blood. In conclusion, pancreatic cancer-derived exosomes (Exo-Mia) suppress the synthesis of GIP and GLP-1 from STC-1cells in vitro by down-regulating the PCSK1/3. Moreover, it may be the pancreatic juice that transport cancer-derived exosomes to target cells (K and L cells) in the gut.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-4750"}
{"PMID":27080237,"Year":2016,"Title":"Stratification of Digestive Cancers with Different Pathological Features and Survival Outcomes by MicroRNA Expression.","Abstract":"MicroRNAs (miRNAs) are aberrantly expressed in virtually all cancer types, including digestive cancers. Herein, we aggregated and systematically analyzed miRNA expression profiles of 1765 tumor samples, including esophageal, gastric, liver, pancreatic, colon and rectal cancers, obtained through small RNA sequencing by The Cancer Genome Atlas. We found that digestive cancers of different tissue origins could be differentiated according to their miRNA expression profiles. In particular, esophageal squamous cell carcinoma and esophageal adenocarcinoma exhibited distinct miRNA expression patterns. Thirteen (e.g. miR-135b, miR-182) and sixteen (e.g. miR-139, miR-133a-1, miR-490) miRNAs were commonly upregulated and downregulated in more than four cancer types, respectively. Pertinent to pathological features, low miR-181d expression was associated with microsatellite instability in colon and gastric cancers whereas low miR-106a expression was associated with hepatitis B virus infection in hepatocellular carcinoma. Progression in colon cancer could also be predicted by low let-7f-2 and high miR-106a expression. Molecular subtypes with distinct prognostic outcomes independent of tumor-node-metastasis staging were identified in hepatocellular carcinoma and colon cancer. In total, 4 novel and 6 reported associations between specific miRNAs and patients' survival were identified. Collectively, novel miRNA markers were identified to stratify digestive cancers with different pathological features and survival outcomes.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-135"}
{"PMID":22851141,"Year":2012,"Title":"Prognostic microRNAs in cancer tissue from patients operated for pancreatic cancer--five microRNAs in a prognostic index.","Abstract":"BACKGROUND: The aim of the present study was to identify a panel of microRNAs (miRNAs) that can predict overall survival (OS) in non micro-dissected cancer tissues from patients operated for pancreatic cancer (PC). METHODS: MiRNAs were purified from formalin-fixed paraffin embedded (FFPE) cancer tissue from 225 patients operated for PC. Only a few of those patients received adjuvant chemotherapy. Expressions of miRNAs were determined with the TaqMan MicroRNA Array v2.0. Two statistical methods, univariate selection and the Lasso (Least Absolute Shrinkage and Selection Operator) method, were applied in conjunction with the Cox proportional hazard model to relate miRNAs to OS. RESULTS: High expression of miR-212 and miR-675 and low expression of miR-148a, miR-187, and let-7g predicted short OS independent of age, gender, calendar year of operation, KRAS mutation status, tumor stage, American Society of Anesthesiologists (ASA) score, localization (not miR-148a), and differentiation of tumor. A prognostic index (PI) based on these five miRNAs was calculated for each patient. The median survival was 1.09 years (Confidence Interval [CI] 0.98-1.43) for PI > median PI compared to 2.23 years (CI 1.84-4.36) for PI < median. MiR-212, miR-675, miR-187, miR-205, miR-944, miR-431, miR-194, miR-148a, and miR-769-5p showed the strongest prediction ability by the Lasso method. Thus miR-212, miR-675, miR-187, and miR-148a were predictors for OS in both statistical methods. CONCLUSIONS: The combination of five miRNAs expression in non micro-dissected FFPE PC tissue can identify patients with short OS after radical surgery. The results are independent of chemotherapy treatment. Patients with a prognostic index > median had a very short median OS of only 1 year.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-944"}
{"PMID":25742499,"Year":2015,"Title":"miR-186 and 326 predict the prognosis of pancreatic ductal adenocarcinoma and affect the proliferation and migration of cancer cells.","Abstract":"MicroRNAs can function as key tumor suppressors or oncogenes and act as biomarkers for cancer diagnosis or prognosis. Although high-throughput assays have revealed many miRNA biomarkers for pancreatic ductal adenocarcinoma (PDAC), only a few have been validated in independent populations or investigated for functional significance in PDAC pathogenesis. In this study, we correlated the expression of 36 potentially prognostic miRNAs within PDAC tissue with clinico-pathological features and survival in 151 Chinese patients. We then analyzed the functional roles and target genes of two miRNAs in PDAC development. We found that high expression of miR-186 and miR-326 predict poor and improved survival, respectively. miR-186 was over-expressed in PDAC patients compared with controls, especially in patients with large tumors (>2 cm), lymph node metastasis, or short-term survival (< 24 months). In contrast, miR-326 was down-regulated in patients compared with controls and displayed relatively increased expression in the patients with long-term survival or without venous invasion. Functional experiments revealed that PDAC cell proliferation and migration was decreased following inhibition and enhanced following over-expression of miR-186. In contrast, it was enhanced following inhibition and decreased after over-expression of miR-326. A luciferase assay indicated that miR-186 can bind directly to the 3'-UTR of NR5A2 to repress gene expression. These findings suggest that miR-186 over-expression contributes to the invasive potential of PDAC, likely via suppression of NR5A2, thereby leading to a poor prognosis; high miR-326 expression prolongs survival likely via the decreasing invasive potential of PDAC cells. These two miRNAs can be used as markers for clinical diagnosis and prognosis, and they represent therapeutic targets for PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-186"}
{"PMID":28967637,"Year":2017,"Title":"Anti-cancer efficiency of natural killer cells differentiated from human adipose tissue-derived mesenchymal stem cells and transfected with miRNA150.","Abstract":"AIM: The aim of this study is to investigate the effects of miR150 transfection on NK-like cells differentiated from adipose tissue derived mesenchymal stem cells (AD-MSCs). METHODS: NK-like cells were differentiated from AD-MSCs and activated by miR150 transfection. Transfected/non-transfected NK-like cells were characterized by immunohistochemical and RT-PCR analyzes. Apoptotic efficiency of the transfected/non-transfected NK-like cells on pancreatic cancer cells PANC1 were determined by TUNEL and RT-PCR. RESULTS: In miR150-transfected cells, the increased expression of NK cell-specific genes such as GKMB, KIR2DL2, CD16, CD56, NKG2D, NKp46 and increased immunoreactivity of NK cell-specific surface marker CD314 (NKG2D) were evident. TUNEL assays showed that NK-like cells with/without transfection induced apoptosis in PANC1 cells in the same manner. The decrease in oncogene expression and the increase in the tumor suppressor gene expression in PANC1 cells upon co-culture with NK-like cells differentiated from AD-MSCs were more prominent following miRNA150 transfection. CONCLUSION: It was shown in vitro that NK-like cells could be obtained by differentiation from AD-MSCs and their efficiency could be increased via miR150 transfection. The results are encouraging for further clinical studies in improvement of immunotherapeutic approaches for cancer therapy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-150"}
{"PMID":31080555,"Year":2019,"Title":"MicroRNA profiling of pancreatic ductal adenocarcinoma (PDAC) reveals signature expression related to lymph node metastasis.","Abstract":"Lymph node (LN) metastasis occurs frequently in pancreatic ductal adenocarcinoma (PDAC), representing an advanced disease stage and independently predicting patient survival. Current nodal staging is inadequate preoperatively and even less so postoperatively, and molecular biomarkers are needed to improve prognostication and selection of therapy. Recent data have suggested important roles of miRNAs in PDAC tumorigenesis and progression. The aim of the present study was to identify miRNA expression signature for nodal spread in PDAC patients. Using PDAC human tissue specimens, we identified 39 miRNAs which were differently expressed in LN positive compared to LN negative PDAC samples. Of them, six miRNAs have been reported to play a role in cancer invasion and metastasis. A high versus low six- miRNA signature score was predictive of LN metastasis in the PDAC validation cohort. We demonstrated a similar expression pattern of four out of the six miRNAs in the plasma of PDAC patients. The results of our in-vitro studies revealed that miR-141 and miR-720 are involved in the process of epithelial to mesenchymal-transition in PDAC. These miRNAs significantly inhibited in vitro proliferation, migration and invasion of PDAC cells as evidence by gain- and loss- of function studies, specifically, via ZEB-1 and TWIST1 transcription factors, as well as through the activation of the MAP4K4/JNK signaling pathway.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-141"}
{"PMID":26121640,"Year":2015,"Title":"Salivary MicroRNA in Pancreatic Cancer Patients.","Abstract":"BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer death in Western countries, with the lowest 1-year survival rate among commonly diagnosed cancers. Reliable biomarkers for pancreatic cancer diagnosis are lacking and are urgently needed to allow for curative surgery. As microRNA (miRNA) recently emerged as candidate biomarkers for this disease, we explored in the present pilot study the differences in salivary microRNA profiles between patients with pancreatic tumors that are not eligible for surgery, precancerous lesions, inflammatory disease or cancer-free patients as a potential early diagnostic tool. METHODS: Whole saliva samples from patients with pancreatic cancer (n = 7), pancreatitis (n = 4), IPMN (n = 2), or healthy controls (n = 4) were obtained during endoscopic examination. After total RNA isolation, expression of 94 candidate miRNAs was screened by q(RT)PCR using Biomark Fluidgm. Human-derived pancreatic cancer cells were xenografted in athymic mice as an experimental model of pancreatic cancer. RESULTS: We identified hsa-miR-21, hsa-miR-23a, hsa-miR-23b and miR-29c as being significantly upregulated in saliva of pancreatic cancer patients compared to control, showing sensitivities of 71.4%, 85.7%, 85,7% and 57%, respectively and excellent specificity (100%). Interestingly, hsa-miR-23a and hsa-miR23b are overexpressed in the saliva of patients with pancreatic cancer precursor lesions. We found that hsa-miR-210 and let-7c are overexpressed in the saliva of patients with pancreatitis as compared to the control group, with sensitivity of 100% and 75%, and specificity of 100% and 80%, respectively. Last hsa-miR-216 was upregulated in cancer patients as compared to patients diagnosed with pancreatitis, with sensitivity of 50% and specificity of 100%. In experimental models of PDAC, salivary microRNA detection precedes systemic detection of cancer cells markers. CONCLUSIONS: Our novel findings indicate that salivary miRNA are discriminatory in pancreatic cancer patients that are not eligible for surgery. In addition, we demonstrate in experimental models that salivary miRNA detection precedes systemic detection of cancer cells markers. This study stems for the use of salivary miRNA as biomarker for the early diagnosis of patients with unresectable pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"let-7"}
{"PMID":26166038,"Year":2015,"Title":"miR-15b promotes epithelial-mesenchymal transition by inhibiting SMURF2 in pancreatic cancer.","Abstract":"The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis. We report here that silencing SMURF2 (SMAD specific E3 ubiquitin protein ligase 2) promoted EMT in HPDE6c7 normal pancreas cells and overexpression of SMURF2 inhibited TGF-beta-mediated EMT in the cells. Subsequent studies showed that SMURF2 was downregulated in pancreatic cancer tissues and it promoted mesenchymal-epithelial transition (MET) in pancreatic cancer cells as well as its expression negatively associated with gemcitabine-resistance, but it did not alter cell viability, cell cycle and cell senescence. In addition, we demonstrated that miR15b degraded SMURF2 and its overexpression promoted EMT in pancreatic cancer, and its expression was associated with metastasis in the disease. Elucidating molecular mechanism of EMT in pancreatic cancer not only will help us to further understand the pathogenesis and progression of the disease, but also offers new targets for effective therapies.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-15"}
{"PMID":24444603,"Year":2014,"Title":"Upregulated miR-106a plays an oncogenic role in pancreatic cancer.","Abstract":"Carcinogenesis is a complex process during which cells undergo genetic and epigenetic alterations. MicroRNAs control gene expression by negatively regulating protein-coding mRNAs. Several reports demonstrated that miR-106a is up-regulated in gastric and colorectal cancers and promotes tumor progression. In contrast, in glioma miR-106a plays the role of a tumor suppressor gene rather than an oncogene. Here we demonstrate that a high level of miR-106a expression is present in pancreatic cancer. Furthermore, our investigation shows that miR-106a has an oncogenic role in pancreatic tumorigenesis by promoting cancer cell proliferation, epithelial-mesenchymal transition and invasion by targeting tissue inhibitors of metalloproteinase 2 (TIMP-2). MiR-106a could be a critical therapeutic target in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-106"}
{"PMID":23335963,"Year":2013,"Title":"Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: role of LIN-28 and SET oncoprotein.","Abstract":"Overexpression of ribonucleotide reductase subunit M2 (RRM2), involved in deoxyribonucleotide synthesis, drives the chemoresistance of pancreatic cancer to nucleoside analogs (e.g., gemcitabine). While silencing RRM2 by synthetic means has shown promise in reducing chemoresistance, targeting endogenous molecules, especially microRNAs (miRNAs), to advance chemotherapeutic outcomes has been poorly explored. Based on computational predictions, we hypothesized that the let-7 tumor suppressor miRNAs will inhibit RRM2-mediated gemcitabine chemoresistance in pancreatic cancer. Reduced expression of the majority of let-7 miRNAs with an inverse relationship to RRM2 expression was identified in innately gemcitabine-resistant pancreatic cancer cell lines. Direct binding of let-7 miRNAs to the 3' UTR of RRM2 transcripts identified post-transcriptional regulation of RRM2 influencing gemcitabine chemosensitivity. Intriguingly, overexpression of human precursor-let-7 miRNAs led to differential RRM2 expression and chemosensitivity responses in a poorly differentiated pancreatic cancer cell line, MIA PaCa-2. Defective processing of let-7a precursors to mature forms, in part, explained the discrepancies observed with let-7a expressional outcomes. Consistently, the ratios of mature to precursor let-7a were progressively reduced in gemcitabine-sensitive L3.6pl and Capan-1 cell lines induced to acquire gemcitabine resistance. Besides known regulators of let-7 biogenesis (e.g., LIN-28), short hairpin RNA library screening identified several novel RNA binding proteins, including the SET oncoprotein, to differentially impact let-7 biogenesis and chemosensitivity in gemcitabine-sensitive versus -resistant pancreatic cancer cells. Further, LIN-28 and SET knockdown in the cells led to profound reductions in cellular proliferation and colony-formation capacities. Finally, defective processing of let-7a precursors with a positive correlation to RRM2 overexpression was identified in patient-derived pancreatic ductal adenocarcinoma (PDAC) tissues. These data demonstrate an intricate post-transcriptional regulation of RRM2 and chemosensitivity by let-7a and that the manipulation of regulatory proteins involved in let-7a transcription/processing may provide a mechanism for improving chemotherapeutic and/or tumor growth control responses in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"let-7"}
{"PMID":28685847,"Year":2018,"Title":"MicroRNA-300 promotes apoptosis and inhibits proliferation, migration, invasion and epithelial-mesenchymal transition via the Wnt/beta-catenin signaling pathway by targeting CUL4B in pancreatic cancer cells.","Abstract":"The study aims to verify the hypothesis that up-regulation of microRNA-300 (miR-300) targeting CUL4B promotes apoptosis and suppresses proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells by regulating the Wnt/beta-catenin signaling pathway. Pancreatic cancer tissues and adjacent tissues were collected from 110 pancreatic cancer patients. Expression of miR-300, CUL4B, Wnt, beta-catenin, E-cadherin, N-cadherin, Snail, GSK-3beta, and CyclinD1 were detected using qRT-PCR and Western blot. CFPAC-1, Capan-1, and PANC-1 were classified into blank, negative control (NC), miR-300 mimics, miR-300 inhibitors, siRNA-CUL4B, and miR-300 inhibitors + siRNA-CUL4B groups. The proliferation, migration, invasion abilities, the cell cycle distribution, and apoptosis rates were measured in CCK-8 and Transwell assays. Pancreatic cancer tissues showed increased CUL4B expression but decreased miR-300 expression. When miR-300 was lowly expressed, CUL4B was upregulated which in-turn activated the Wnt/beta-catenin pathway to protect the beta-catenin expression and thus induce EMT. When miR-300 was highly expressed, CUL4B was downregulated which in-turn inhibited the Wnt/beta-catenin pathway to prevent EMT. Weakened cell migration and invasion abilities and enhanced apoptosis were observed in the CUL4B group. The miR-300 inhibitors group exhibited an evident increase in growth rate accompanied the largest tumor volume. Smaller tumor volume and slower growth rate were observed in the miR-300 mimics and siRNA-CUL4B group. Our study concludes that lowly expressed miR-300 may contribute to highly expressed CUL4B activating the Wnt/beta-catenin signaling pathway and further stimulating EMT, thus promoting proliferation and migration but suppressing apoptosis of pancreatic cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-300"}
{"PMID":28259961,"Year":2017,"Title":"MicroRNA-7 functions as a tumor-suppressor gene by regulating ILF2 in pancreatic carcinoma.","Abstract":"Interleukin enhancer binding factor 2 (ILF2) has been found to be markedly upregulated in pancreatic carcinoma and is involved in the pathogenesis of pancreatic carcinoma. Thus, ILF2 may be a potential target for therapy. Yet, the regulatory mechanisms of ILF2 in pancreatic carcinoma remain largely elusive. In the present study, we demonstrated that ILF2 functioned as an oncogene and regulated epithelial-mesenchymal transition (EMT)-associated genes in pancreatic carcinoma PANC-1 cells. MicroRNA-7 (miR-7) suppressed ILF2 mRNA expression and the protein level in PANC-1 cells. Contrary to ILF2, miRNA-7 functioned as a tumor-suppressor gene and negatively regulated EMT-associated genes in the PANC-1 cells. Curcumin, a polyphenol natural product isolated from the rhizome of the plant Curcuma longa, has emerged as a promising anticancer therapeutic agent. We found that treatment with curcumin increased miR-7 expression and suppressed ILF2 protein in the PANC-1 cells. Thus, we identified ILF2 as a new downstream target gene of curcumin. The results revealed that ILF2 is regulated by miR-7 and suggest that downregulation of miR-7 may be an important factor for the ILF2 overexpression in pancreatic carcinoma.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-7"}
{"PMID":27153315,"Year":2016,"Title":"IGF2BP2 promotes colorectal cancer cell proliferation and survival through interfering with RAF-1 degradation by miR-195.","Abstract":"Insulin-like growth factor 2 (IGF2) mRNA-binding protein 2 (IGF2BP2) is a post-transcriptional regulatory factor implicated in mRNA localization, stability, and translational control. However, the role of IGF2BP2 regulation in colorectal cancer (CRC) and its underlying mechanism remain elusive. In this study, we found that IGF2BP2 expression is markedly increased in CRC tissues. Notably, IGF2BP2 overexpression strikingly enhanced the proliferation and survival of CRC cells in vitro, whereas its shRNA-mediated silencing resulted in the opposite. Molecular function analyses revealed that IGF2BP2 regulates RAF1 expression through blocking its degradation by miR-195. These results identify IGF2BP2 as a post-transcriptional regulatory mRNA-binding factor that contributes to CRC carcinogenesis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-195"}
{"PMID":22042419,"Year":2011,"Title":"[MicroRNA expression pattern in intraductal papillary mucinous neoplasm].","Abstract":"BACKGROUND/AIMS: Intraductal papillary mucinous neoplasms (IPMN) are precursor lesions of fatal pancreatic cancer. Physiological function of microRNA is to regulate the stability and translation of mRNA. The aberrant microRNA expression is commonly observed in many cancers. The aim of this study was to analyze the expression pattern of microRNA in IPMN and evaluate the role of the microRNA. METHODS: Using two paraffin-embedded IPMN tissues, microRNA expression of normal tissue, IPMN adenoma and carcinoma were compared by cDNA-mediated annealing, selection, extension and ligation microarray assay. Using real time PCR, expression levels of aberrantly up-regulated microRNAs were assessed in another 20 IPMNs, four pancreatic cancer cell lines (Panc1, MiaPaCa-2, XPA-3, BxPC-3) and immortalized pancreatic ductal cell line (HPNE). Effect of suppressing highly over-expressed two microRNAs in pancreatic cancer cell lines with anti-microRNA inhibitors were evaluated using CCK-8 assay. RESULTS: Among aberrantly expressed 122 microRNAs in IPMN, miR-552, miR-25*, miR-183, miR-1300, miR-196a, miR-182*, and miR-30c-1* were consistently increased more than 3-fold. On average, miR-196a and miR-183 increased 10,824 folds and 26,519 folds in four pancreatic cancer cell lines compared with HPNE. These two microRNAs were also over-expressed in 20 IPMNs compared with HPNE. After applying anti-miRNA inhibitors, cell survival of four pancreatic cancer cell lines decreased by 24.5% with anti-miR-196a and by 14.2% with anti-miR-183 on average. CONCLUSIONS: Aberrant expression of 122 microRNAs was observed in IPMN. Two microRNAs, miR-196a and miR-183-increased in IPMN and pancreatic cancer cell lines compared with immortalized dancreatic ductal cell line. The inhibitions of these microRNAs repressed cell proliferation of pancreatic cancer cell lines. (Korean J Gastroenterol 2011;58:190-200).","Language":"kor","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1300"}
{"PMID":26918939,"Year":2016,"Title":"MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor.","Abstract":"Pancreatic stellate cells (PSCs) are the key precursor cells for cancer-associated fibroblasts (CAFs) in pancreatic tumor stroma. In this study, we explored miRNA as therapeutic targets in tumor stroma and found miR-199a-3p and miR-214-3p induced in patient-derived pancreatic CAFs and TGF-beta-activated human PSCs (hPSCs). Inhibition of miR-199a/-214 using hairpin inhibitors significantly inhibited TGFbeta-induced differentiation markers (e.g. alpha-SMA, collagen, PDGFbetaR), migration and proliferation. Furthermore, heterospheroids of Panc-1 and hPSCs attained smaller size with hPSCs transfected with anti-miR-199a/-214 compared to control anti-miR. The conditioned medium obtained from TGFbeta-activated hPSCs induced tumor cell growth and endothelial cell tube formation. Interestingly, these inductions were abrogated in hPSCs transfected with anti-miR-199a or miR-214. Moreover, IPA analyses revealed signaling pathways related to miR-199a (TP53, mTOR, Smad1) and miR-214 (PTEN, Bax, ING4). Taken together, this study reveals miR-199a-3p and miR-214-3p as major regulators of PSC activation and PSC-induced pro-tumoral effects, representing them as key therapeutic targets in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-214"}
{"PMID":29962816,"Year":2018,"Title":"Novel serum microRNAs panel on the diagnostic and prognostic implications of hepatocellular carcinoma.","Abstract":"AIM: To determine a panel of serum microRNAs (miRNAs) that could be used as novel biomarkers for diagnosis of hepatocellular carcinoma (HCC). METHODS: We initially screened 9 out of 754 serum miRNAs by TaqMan Low Density Array in two pooled samples respectively from 35 HCC and 35 normal controls, and then validated individually by RT-qPCR in another 114 patients and 114 controls arranged in two phases. The changes of the selected miRNAs after operation and their prognostic value were examined. RESULTS: miR-375, miR-10a, miR-122 and miR-423 were found to be significantly higher in HCC than in controls (P < 0.0001), and the area under the receiver-operating-characteristic curve for the 4-miRNA panel was 0.995 (95%CI: 0.985-1). All the four miRNAs were significantly reduced after surgical removal of the tumors (P < 0.0001), while still higher than normal controls (at least P < 0.05). CONCLUSION: The four serum miRNAs (miR-375, miR-10a, miR-122 and miR-423) could potentially serve as novel biomarkers for the diagnostic and prognostic of HCC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-375"}
{"PMID":21632853,"Year":2011,"Title":"Clinical significance of miR-146a in gastric cancer cases.","Abstract":"PURPOSE: The profiles of microRNAs change significantly in gastric cancer. MiR-146a is reported to be a tumor suppressor in pancreatic cancer, breast cancer, and prostate cancer. We investigated the clinical significance of miR-146a in gastric cancer, in particular focusing on hypothetical miR-146a target genes, such as epidermal growth factor receptor (EGFR) and interleukin-1 receptor-associated kinase (IRAK1). EXPERIMENTAL DESIGN: We examined miR-146a levels in 90 gastric cancer samples by q-real-time (qRT)-PCR and analyzed the association between miR-146a levels and clinicopathologic factors and prognosis. The regulation of EGFR and IRAK1 by miR-146a was examined with miR-146a-transfected gastric cancer cells. Moreover, we analyzed the association between miR-146a levels and the G/C single nucleotide polymorphism (SNP) within pre-miR-146a seed sequences in 76 gastric cancer samples, using direct sequencing of genomic DNA. RESULTS: In 90 clinical samples of gastric cancer, miR-146a levels in cancer tissues were significantly lower than those in the corresponding noncancerous tissue (P < 0.001). Lower levels of miR-146a were associated with lymph node metastasis and venous invasion (P < 0.05). Moreover, a lower level of miR-146a was an independent prognostic factor for overall survival (P = 0.003). Ectopic expression of miR-146a inhibited migration and invasion and downregulated EGFR and IRAK1 expression in gastric cancer cells. In addition, G/C SNP within the pre-miR-146a seed sequence significantly reduced miR-146a levels in the GG genotype compared with the CC genotype. CONCLUSIONS: MiR-146a contains an SNP, which is associated with mature miR-146a expression. MiR-146a targeting of EGFR and IRAK1 is an independent prognostic factor in gastric cancer cases.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-146"}
{"PMID":27624777,"Year":2016,"Title":"Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFbeta1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p.","Abstract":"The identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacologic inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their antitumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, significantly reprograms noncoding microRNA (miRNA) expression and dampens TGFbeta1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer. In particular, miR-663a and miR-4787-5p were identified as PDAC-downregulated miRNAs that were reactivated by DZNep to directly target TGFbeta1 for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p reduced TGFbeta1 synthesis and secretion in PDAC cells and partially phenocopied DZNep's EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRNAs counteracted them. DZNep, miR-663a, and miR-4787-5p reduced tumor burden in vivo and metastases in an orthotopic mouse pancreatic tumor model. Taken together, these findings suggest the epigenetic reprogramming of miRNAs by synthetic histone methylation reversal agents as a viable approach to attenuate TGFbeta1-induced EMT features in human PDAC and uncover putative miRNA targets involved in the process. IMPLICATIONS: The findings support the potential for synthetic histone methylation reversal agents to be included in future epigenetic-chemotherapeutic combination therapies for pancreatic cancer. Mol Cancer Res; 14(11); 1124-35. (c)2016 AACR.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-663"}
{"PMID":31015415,"Year":2019,"Title":"Excessive miR-25-3p maturation via N(6)-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression.","Abstract":"N(6)-methyladenosine (m(6)A) modification is an important mechanism in miRNA processing and maturation, but the role of its aberrant regulation in human diseases remained unclear. Here, we demonstrate that oncogenic primary microRNA-25 (miR-25) in pancreatic duct epithelial cells can be excessively maturated by cigarette smoke condensate (CSC) via enhanced m(6)A modification that is mediated by NF-kappaB associated protein (NKAP). This modification is catalyzed by overexpressed methyltransferase-like 3 (METTL3) due to hypomethylation of the METTL3 promoter also caused by CSC. Mature miR-25, miR-25-3p, suppresses PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2), resulting in the activation of oncogenic AKT-p70S6K signaling, which provokes malignant phenotypes of pancreatic cancer cells. High levels of miR-25-3p are detected in smokers and in pancreatic cancers tissues that are correlated with poor prognosis of pancreatic cancer patients. These results collectively indicate that cigarette smoke-induced miR-25-3p excessive maturation via m(6)A modification promotes the development and progression of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-25"}
{"PMID":30651845,"Year":2019,"Title":"Restoration of miRNA-148a in pancreatic cancer reduces invasion and metastasis by inhibiting the Wnt/beta-catenin signaling pathway via downregulating maternally expressed gene-3.","Abstract":"Various microRNAs (miRNA) have been recognized potential novel tumor markers and have a critical role in cancer development and progression. Recently, methylation of miRNA-148a was identified as a crucial biochemical process in the progression of cancer. However, its potential role and in pancreatic cancer as well as the underlying mechanisms have remained largely elusive. The present study investigated the potential antitumor effect of miR-148a as well as its impact on invasion and metastasis in pancreatic cancer. It was found that the expression of miRNA-148a and the potential predictive biomarker maternally expressed gene-3 (MEG-3) were obviously decreased in human pancreatic cancer tissues compared with those in adjacent non-tumorous tissues. Furthermore, miR-148a was found to be downregulated in pancreatic cancer cell lines compared with normal pancreatic cells through promoter methylation. An MTT assay and a clonogenic assay demonstrated that restoration of miRNA-148a inhibited the proliferation and colony formation of pancreatic cancer cells. In addition, miR-148a transduction led to the upregulation of MEG-3 expression and promoted apoptosis of pancreatic cancer cells. Western blot analysis revealed that transduction of miR-148a markedly decreased the expression levels of C-myc, cyclin D1 and beta-catenin in pancreatic cancer cells. Methylation of miR-148a not only decreased the endogenous beta-catenin levels but also inhibited the nuclear translocation of beta-catenin to delay cell cycle progression. Furthermore, ectopic miR-148a methylation inhibited pancreatic cancer cell migration and invasion via causing an upregulation of MEG-3 expression. Most importantly, ectopic overexpression of miR-148a in pancreatic cancer cells inhibited tumor formation in an animal experiment. Taken together, miR-148a methylation is a crucial regulatory process to inhibit the proliferation and invasion of pancreatic cancer cells, and transduction of miR-148a suppressed the proliferation of pancreatic cancer cells through negative regulation of the Wnt/beta-catenin signaling pathway. The findings of the present study suggested that miRNA-148a acts as a tumor suppressor in pancreatic cancer and may contribute to the development of novel treatments for pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-148"}
{"PMID":23831622,"Year":2013,"Title":"miR-210 regulates the interaction between pancreatic cancer cells and stellate cells.","Abstract":"There is accumulating evidence that pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer. microRNAs (miRNAs) are small non-coding RNAs acting as negative regulators of gene expression at the post-transcriptional level. This study aimed to clarify the role of miRNAs in the interaction between PSCs and pancreatic cancer cells. Pancreatic cancer cells were mono-cultured or indirectly co-cultured with PSCs. miRNAs were prepared, and Agilent's miRNA microarray containing probes for 904 human miRNAs was used to identify differentially expressed miRNAs. miR-210 was identified as an upregulated miRNA by co-culture with PSCs. Conditioned media of PSCs activated ERK and Akt, but not hypoxia-inducible factor-1alpha pathway. PSCs-induced miR-210 upregulation was inhibited by inhibitors of ERK and PI3K/Akt pathways. Inhibition of miR-210 expression decreased migration, decreased the expression of vimentin and snai-1, and increased the membrane-associated expression of beta-catenin in Panc-1 cells co-cultured with PSCs. In conclusion, our results suggest a novel role of miR-210 in the interaction between PSCs and pancreatic cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-210"}
{"PMID":25576058,"Year":2015,"Title":"Metformin and Rapamycin Reduce Pancreatic Cancer Growth in Obese Prediabetic Mice by Distinct MicroRNA-Regulated Mechanisms.","Abstract":"Metformin treatment is associated with a decreased risk and better prognosis of pancreatic cancer (PC) in patients with type 2 diabetes, but the mechanism of metformin's PC growth inhibition in the context of a prediabetic state is unknown. We used a Panc02 pancreatic tumor cell transplant model in diet-induced obese (DIO) C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC growth, glucose regulation, mTOR pathway signaling, and candidate microRNA (miR) expression. In DIO/prediabetic mice, metformin and rapamycin significantly reduced pancreatic tumor growth and mTOR-related signaling. The rapamycin effects centered on decreased mTOR-regulated growth and survival signaling, including increased expression of let-7b and cell cycle-regulating miRs. Metformin (but not rapamycin) reduced glucose and insulin levels and expression of miR-34a and its direct targets Notch, Slug, and Snail. Metformin also reduced the number and size of Panc02 tumor spheres in vitro and inhibited the expression of Notch in spheroids. Our results suggest that metformin and rapamycin can both inhibit pancreatic tumor growth in obese, prediabetic mice through shared and distinct mechanisms. Metformin and direct mTOR inhibitors, alone or possibly in combination, represent promising intervention strategies for breaking the diabetes-PC link.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-34"}
{"PMID":27213352,"Year":2016,"Title":"Predicting MicroRNA Biomarkers for Cancer Using Phylogenetic Tree and Microarray Analysis.","Abstract":"MicroRNAs (miRNAs) are shown to be involved in the initiation and progression of cancers in the literature, and the expression of miRNAs is used as an important cancer prognostic tool. The aim of this study is to predict high-confidence miRNA biomarkers for cancer. We adopt a method that combines miRNA phylogenetic structure and miRNA microarray data analysis to discover high-confidence miRNA biomarkers for colon, prostate, pancreatic, lung, breast, bladder and kidney cancers. There are 53 miRNAs selected through this method that either have potential to involve a single cancer's development or to involve several cancers' development. These miRNAs can be used as high-confidence miRNA biomarkers of these seven investigated cancers for further experiment validation. miR-17, miR-20, miR-106a, miR-106b, miR-92, miR-25, miR-16, miR-195 and miR-143 are selected to involve a single cancer's development in these seven cancers. They have the potential to be useful miRNA biomarkers when the result can be confirmed by experiments.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-17"}
{"PMID":22114139,"Year":2012,"Title":"MicroRNA alterations of pancreatic intraepithelial neoplasias.","Abstract":"PURPOSE: MicroRNA (miRNA) alterations are likely to contribute to the development of pancreatic cancer and may serve as markers for the early detection of pancreatic neoplasia. EXPERIMENTAL DESIGN: To identify the miRNA alterations that arise during the development of pancreatic cancer, we determined the levels of 735 miRNAs in 34 pancreatic intraepithelial neoplasias (PanIN) and 15 normal pancreatic duct samples isolated by laser capture microdissection using TaqMan miRNA microarrays. Differential expression of selected miRNAs was confirmed by FISH analysis and by quantitative real-time reverse transcription PCR (qRT-PCR) analysis of selected candidate miRNAs in an independent set of PanIN and normal duct samples. RESULTS: We identified 107 aberrantly expressed miRNAs in different PanIN grades compared with normal pancreatic duct samples and 35 aberrantly expressed miRNAs in PanIN-3 lesions compared with normal pancreatic duct samples. These differentially expressed miRNAs included those that have been previously identified as differentially expressed in pancreatic ductal adenocarcinomas (PDAC; including miR-21, miR-200a/b/c, miR-216a/b, miR-217, miR-146a, miR-155, miR-182, miR-196b, miR-203, miR-222, miR-338-3p, miR-486-3p, etc.) as well as miRNAs not previously described as differentially expressed in these lesions (miR-125b, miR-296-5p, miR-183*, miR-603, miR-625/*, miR-708, etc.). miR-196b was the most selectively differentially expressed miRNA in PanIN-3 lesions. CONCLUSIONS: Many miRNAs undergo aberrant expression in PanIN lesions and are likely to be important in the development of PDAC. The miRNAs, such as miR-196b, whose expression is limited to PanIN-3 lesions or pancreatic cancers could be useful as diagnostic markers.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-338"}
{"PMID":26094040,"Year":2015,"Title":"Serum levels of unique miR-551-5p and endothelial-specific miR-126a-5p allow discrimination of patients in the early phase of acute pancreatitis.","Abstract":"OBJECTIVES: Vascular dysfunction is a severe complication which can cause organ ischemia and damage during acute pancreatitis (AP). Laboratory assessment of AP is based on several routine parameters and does not reflect endothelial dysfunction or organ injury. Recently, small non-protein-coding RNAs (miRNAs) have been introduced to laboratory diagnostics as new biomarkers or predictive parameters. Candidate miRNAs (hsa-miR-16-5p, -103a-3p, -122-5p, -126-5p, -148a-5p, -216a-5p, -375, and -551b-5b) were selected to check their possible clinical application in stratification of patients with different AP severity. METHODS: In this observational study, 62 patients with mild (MAP) and 26 with moderate and severe (SAP) acute pancreatitis were included. The control group consisted of 10 age and sex matched subjects. Circulating miRNAs were analyzed in serum using a quantitative real-time PCR method (q-RT-PCR) by means of 3'-locked-nucleic-acid primers. RESULTS: In SAP patients, a significant increase in most of the selected miRNAs (miR-126-5p, -148a-3p, -216a-5p and -551b-5p, and miR-375) was observed when compared to control subjects. In MAP patients, three miRNAs were significantly elevated: endothelial-specific miR-216a-5p, -551b-5p, as well as miR-375 that is highly abundant in pancreas. ROC analysis revealed that miR-126-p and miR-551b-5p can predict AP severity (AUC 0.748, sensitivity 60.0%, specificity 87.1%, p < 0.001) and (AUC 0.716; sensitivity 69.2%, specificity 72.6%, p < 0.001). miR-375 was not relevant (AUC 0.458; sensitivity 55.%, specificity 44.4%). CONCLUSIONS: A pancreatic miRNA signature can be useful for assessment of pancreatic injury in the acute phase of AP. Endothelial dysfunction during AP is reflected by levels of specific circulating miRNAs and may help in patient stratification.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-122"}
{"PMID":24449318,"Year":2014,"Title":"MicroRNA biomarkers in whole blood for detection of pancreatic cancer.","Abstract":"IMPORTANCE: Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis. OBJECTIVES: To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9). DESIGN, SETTING, AND PARTICIPANTS: A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer, 18 patients with chronic pancreatitis, and 69 healthy participants), training cohort (180 patients with pancreatic cancer, 1 patient with chronic pancreatitis, and 199 healthy participants), and validation cohort (86 patients with pancreatic cancer, 7 patients with chronic pancreatitis, and 44 healthy participants); 754 microRNAs were screened in the discovery cohort and 38 microRNAs in the training cohort and 13 microRNAs in the validation cohort. MAIN OUTCOMES AND MEASURES: Identification of microRNA panels (classifiers) for diagnosing pancreatic cancer. RESULTS: The discovery cohort demonstrated that 38 microRNAs in whole blood were significantly dysregulated in patients with pancreatic cancer compared with controls. These microRNAs were tested in the training cohort and 2 diagnostic panels were constructed comprising 4 microRNAs in index I (miR-145, miR-150, miR-223, miR-636) and 10 in index II (miR-26b, miR-34a, miR-122, miR-126*, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p). The test characteristics for the training cohort were index I area under the curve (AUC) of 0.86 (95% CI, 0.82-0.90), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.64 (95% CI, 0.57-0.71); index II AUC of 0.93 (95% CI, 0.90-0.96), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.85 (95% CI, 0.80-0.85); and CA19-9 AUC of 0.90 (95% CI, 0.87-0.94), sensitivity of 0.86 (95% CI, 0.80-0.90), and specificity of 0.99 (95% CI, 0.96-1.00). Performances were strengthened in the validation cohort by combining panels and CA19-9 (index I AUC of 0.94 [95% CI, 0.90-0.98] and index II AUC of 0.93 [95% CI, 0.89-0.97]). Compared with CA19-9 alone, the AUC for the combination of index I and CA19-9 was significantly higher (P = .01). The performance of the panels in patients with stage IA-IIB pancreatic cancer was index I AUC of 0.80 (95% CI, 0.73-0.87); index I and CA19-9 AUC of 0.83 (95% CI, 0.76-0.90); index II AUC of 0.91 (95% CI, 0.87-0.94); and index II and CA19-9 AUC of 0.91 (95% CI, 0.86-0.95). CONCLUSIONS AND RELEVANCE: This study identified 2 diagnostic panels based on microRNA expression in whole blood with the potential to distinguish patients with pancreatic cancer from healthy controls. Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-150"}
{"PMID":23430754,"Year":2013,"Title":"Combined serum CA19-9 and miR-27a-3p in peripheral blood mononuclear cells to diagnose pancreatic cancer.","Abstract":"MicroRNAs are potentially very useful biomarkers in the diagnosis of cancer. We sought to identify specific microRNAs in peripheral blood mononuclear cells (PBMCs) whose levels might facilitate diagnosis of pancreatic cancer. We investigated PBMC microRNA expression in three independent cohorts [healthy, benign pancreatic/peripancreatic diseases (BPD), and pancreatic cancer], comprising a total of 352 participants. First, we used sequencing technology to identify differentially expressed microRNAs in PBMC of pancreatic cancer, BPD, and healthy controls (n = 20 in each group). Then the selected microRNAs were analyzed using the quantitative reverse transcriptase PCR assays in the remaining 292 samples. The predictive value of the microRNAs was evaluated by logistic regression models and the receiver operating characteristic curve (AUC). We found that miR-27a-3p level in PBMCs could discriminate pancreatic cancer from BPD with a sensitivity of 82.2% and specificity of 76.7% (AUC = 0.840; 95% CI, 0.787-0.885%). Combination of PBMC miR-27a-3p and serum CA19-9 levels provided a higher diagnostic accuracy with a sensitivity of 85.3% and specificity of 81.6% (AUC = 0.886; 95% CI, 0.837-0.923%). The satisfactory diagnostic performance of the panel persisted regardless of disease status (AUCs for tumor-node-metastasis stages I-III were 0.881, 0.884, and 0.893, respectively). PBMC miR-27a-3p level represents a potential marker for pancreatic cancer screening. A panel combining serum CA19-9 and PBMC miR-27a-3p level could have considerable clinical value in diagnosing pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-27"}
{"PMID":24246865,"Year":2013,"Title":"[MiR-150-5p inhibits the proliferation and promoted apoptosis of pancreatic cancer cells].","Abstract":"OBJECTIVE: To investigate the role of miR-150-5p in cell proliferation and apoptosis in human pancreatic cancer cell lines. METHODS: The expression of miR-150-5p in pancreatic cancer was detected by real time qPCR analysis in 11 pairs of pancreatic cancer tissue and matched adjacent normal tissue samples and in 4 pancreatic cancer cell lines. PANC-1, MIA PaCa-2,BxPC-3 and AsPC-1 cells were transfected with chemically synthesized MiR-150-5p mimics, and CCK-8 assays was then performed to assess cellular functions. To fully understand the mechanisms by which miR-150-5p exerted its function, cell cycle analysis was performed on MIA PaCa-2 and PANC-1 cells 48 hours after transfection, by incubating with propidium iodide (PI)and subsequently analyzed by fluorescence-activated cell sorting (FACS) . Apoptosis assay was performed on MIA PaCa-2 and PANC-1 cell lines 24 hours after transfection using the Annexin V-FITC Apoptosis Detection Kit I (BD Biosciences) and analyzed by FACS. RESULTS: The expression of miR-150-5p was consistently lower in the pancreatic cancer tissues than in normal tissues, and the miR-150-5p was also down-regulated in pancreatic cancer cell lines (P < 0.05) . MiR-150-5p mimics transfection significantly raised the expression level of miR-150-5p mRNA in PANC-1 and MIA PaCa-2 (P < 0.01) . The CCK-8 proliferation assay showed that cell growth was reduced in 4 pancreatic cancer cell lines (AsPC-1, BxPC-3,MIA PaCa-2, PANC-1) of miR-150-5p transfected cells compared with NC-transfected cells. The inhibition rates were 50.7%, 48.6%, 30.8% and 42.3%, respectively (P < 0.01). The apoptotic rate was increased in cells transfected with miR-150-5p mimics (P < 0.01) . The cell cycle analysis in MIA PaCa-2 indicated that miR-150-5p treatment induced cell cycle arrest in G1 phase with a significant increase in the percentage of cells in G1 phase (P < 0.01), and a reduction of the S-phase cell population in MIA PaCa-2 and PANC-1 (P < 0.01). CONCLUSIONS: MiR-150-5p is down-regulated in pancreatic cancer. Over-expression of miR-150-5p inhibits cell proliferation, blocked the cell cycle, but promotes cell apoptosis in pancreatic cancer cells.","Language":"chi","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-150"}
{"PMID":28239461,"Year":2017,"Title":"Tissue MicroRNA profiles as diagnostic and prognostic biomarkers in patients with resectable pancreatic ductal adenocarcinoma and periampullary cancers.","Abstract":"BACKGROUND: The aim of this study was to validate previously described diagnostic and prognostic microRNA expression profiles in tissue samples from patients with pancreatic cancer and other periampullary cancers. METHODS: Expression of 46 selected microRNAs was studied in formalin-fixed paraffin-embedded tissue from patients with resected pancreatic ductal adenocarcinoma (n = 165), ampullary cancer (n=59), duodenal cancer (n = 6), distal common bile duct cancer (n = 21), and gastric cancer (n = 20); chronic pancreatitis (n = 39); and normal pancreas (n = 35). The microRNAs were analyzed by PCR using the Fluidigm platform. RESULTS: Twenty-two microRNAs were significantly differently expressed in patients with pancreatic cancer when compared to healthy controls and chronic pancreatitis patients; 17 miRNAs were upregulated (miR-21-5p, -23a-3p, -31-5p, -34c-5p, -93-3p, -135b-3p, -155-5p, -186-5p, -196b-5p, -203, -205-5p, -210, -222-3p, -451, -492, -614, and miR-622) and 5 were downregulated (miR-122-5p, -130b-3p, -216b, -217, and miR-375). MicroRNAs were grouped into diagnostic indices of varying complexity. Ten microRNAs associated with prognosis were identified (let-7 g, miR-29a-5p, -34a-5p, -125a-3p, -146a-5p, -187, -205-5p, -212-3p, -222-5p, and miR-450b-5p). Prognostic indices based on differences in expression of 2 different microRNAs were constructed for pancreatic and ampullary cancer combined and separately (30, 5, and 21 indices). CONCLUSION: The study confirms that pancreatic cancer tissue has a microRNA expression profile that is different from that of other periampullary cancers, chronic pancreatitis, and normal pancreas. We identified prognostic microRNAs and microRNA indices that were associated with shorter overall survival in patients with radically resected pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-31"}
{"PMID":28537673,"Year":2017,"Title":"Comprehensive analysis of microRNA/mRNA signature in colon adenocarcinoma.","Abstract":"OBJECTIVE: The goal of our study was to identify the regulatory mechanisms of gene expression mediated by miRNAs and DNA methylation in colon adenocarcinoma (COAD). MATERIALS AND METHODS: The miRNAs and mRNAs expression and DNA methylation data of COAD and adjacent normal tissues were obtained from The Cancer Genome Atlas (TCGA) database. Based on the differentially expressed miRNAs and mRNAs, miRNA-mRNA pairs were obtained by correlation analysis and prediction algorithms. Finally, COAD-specific miRNA-mRNA regulatory network was generated. Additionally, the biological functions of miRNA targets were further revealed by GO and KEGG enrichment analysis. Besides, the correlation analysis between gene expression and DNA methylation was also performed after differential analysis. RESULTS: We identified 55 differentially expressed miRNAs and 1291 differentially expressed mRNAs in COAD compared with adjacent normal tissues. We observed a global miRNA up-regulation in tumors. A total of 58 miRNA-mRNA pairs were not only predicted by algorithms but also negatively correlated. The increased expression of has-mir-141, -19a, -20a 19b-1, 19b-2, 16, 590 and -335 were closely associated with the carcinogenesis of COAD. Functional enrichment analysis showed that the miRNA targets were significantly enriched in pancreatic secretion, salivary secretion, gastric acid secretion and bile secretion. Regarding the regulatory role of DNA methylation, we identified 11 genes whose expressions were negatively correlated with DNA methylation level. Among those genes, MSX1 and KRT7 were down-regulated and hypermethylated in COAD compared with adjacent normal tissues. CONCLUSIONS: These eight miRNAs (has-mir-141, -19a, -20a 19b-1, 19b-2, 16, 590 and -335) and two genes (MSX1 and KRT7) may play a role in the process of COAD. These findings highlighted the potential regulatory mechanisms of miRNA and DNA methylation on mRNA expression in COAD carcinogenesis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-20"}
{"PMID":24404812,"Year":2014,"Title":"Alteration of the microRNA expression profile during the activation of pancreatic stellate cells.","Abstract":"OBJECTIVE. Pancreatic stellate cells (PSCs) play a pivotal role in the pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. In response to pancreatic injury or inflammation, PSCs are activated to myofibroblast-like cells. MicroRNA (miRNA) is a small RNA, consisting of 17-25 nucleotides, which targets 3'-untranslated region sequences of mRNA. miRNAs regulate a variety of cell functions such as cell proliferation, differentiation, and carcinogenesis. We examined here whether the miRNA expression profiles are altered during the activation of PSCs. MATERIALS AND METHODS. Rat PSCs were isolated from the pancreas tissue of male Wistar rats. PSCs were activated in vitro by culture in serum-containing medium. miRNAs were prepared from quiescent (day 1) PSCs and culture-activated (day 14) PSCs. Agilent's miRNA microarray containing probes for 680 miRNAs was used to identify differentially expressed miRNAs. Ingenuity Pathway Analysis (IPA) was used for the integrated analysis of altered miRNAs. RESULTS. Upon activation, 42 miRNAs were upregulated (>2.0-fold) and 42 miRNAs were downregulated (<0.5-fold). Upregulated miRNAs included miR-31, miR-143, and miR-221. Downregulated miRNAs included miR-126, miR-146a, and miR-150. IPA revealed the most impacted biological processes including cellular development, cellular growth, and cell movement. Interestingly, IPA identified 22 miRNAs affected both in pancreatic cancer and PSC activation. The top network generated by IPA revealed the interactions of altered miRNAs with signaling pathways such as p38 mitogen-activated protein kinase, extracellular-signal-regulated kinase, and Smad2/3. CONCLUSIONS. Our results suggest a novel role of miRNAs in the activation of PSCs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-31"}
{"PMID":24026406,"Year":2014,"Title":"MicroRNA-92a functions as an oncogene in colorectal cancer by targeting PTEN.","Abstract":"BACKGROUND: Our previous studies show that microRNA-92a (miR-92a) is overexpressed in colorectal cancer (CRC) and is thought to be correlated with the development of the cancer. However, its biological role in CRC remains poorly understood. AIMS: The aim of the study was to determine the role of miR-92a and to elucidate its regulatory mechanism in CRC. METHODS: The expression levels of miR-92a and phosphatase and tensin homologue (PTEN) were detected by qRT-PCR and western blot. MTT, migration and invasion assays were used to examine the proliferation, migration and invasion of pre-miR-92a transfected SW480 cells, and a mouse model was used to investigate tumorigenesis. In addition, the regulation of PTEN by miR-92a was evaluated by qRT-PCR, western blot and luciferase reporter assays. RESULTS: The expression of miR-92a was significantly up-regulated in the tissues of CRC patients with lymph node metastasis. The ectopic expression of miR-92a enhanced CRC cell proliferation, migration and invasion. Similar results were found in xenograft assay performed in nude mice. Up-regulation of miR-92a induced EMT in CRC cells. There was an inverse correlation between the levels of miR-92a and PTEN in CRC tissues. The overexpression of miR-92a in CRC cells decreased PTEN expression at the translational level, and decreased PTEN-driven luciferase-reporter activity. CONCLUSIONS: Our results demonstrated that miR-92a induced EMT and regulated cell growth, migration and invasion in the SW480 cells, at least partially, via suppression of PTEN expression. MiR-92a may serve as a novel therapeutic target in colorectal cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-92"}
{"PMID":22878649,"Year":2012,"Title":"MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma.","Abstract":"MicroRNAs have potential as diagnostic cancer biomarkers. The aim of this study was (1) to define microRNA expression patterns in formalin-fixed parafin-embedded tissue from pancreatic ductal adenocarcinoma, ampullary adenocarcinoma, normal pancreas and chronic pancreatitis without using micro-dissection and (2) to discover new diagnostic microRNAs and combinations of microRNAs in cancer tissue. The expression of 664 microRNAs in tissue from 170 pancreatic adenocarcinomas and 107 ampullary adenocarcinomas were analyzed using a commercial microRNA assay. Results were compared with chronic pancreatitis, normal pancreas and duodenal adenocarcinoma. In all, 43 microRNAs had higher and 41 microRNAs reduced expression in pancreatic cancer compared with normal pancreas. In all, 32 microRNAs were differently expressed in pancreatic adenocarcinoma compared with chronic pancreatitis (17 higher; 15 reduced). Several of these microRNAs have not before been related to diagnosis of pancreatic cancer (eg, miR-492, miR-614, miR-622). MiR-614, miR-492, miR-622, miR-135b and miR-196 were most differently expressed. MicroRNA profiles of pancreatic and ampullary adenocarcinomas were correlated (0.990). MicroRNA expression profiles for pancreatic cancer described in the literature were consistent with our findings, and the microRNA profile for pancreatic adenocarcinoma (miR-196b-miR-217) was validated. We identified a more significant expression profile, the difference between miR-411 and miR-198 (P=2.06 x 10(-54)) and a diagnostic LASSO classifier using 19 microRNAs (sensitivity 98.5%; positive predictive value 97.8%; accuracy 97.0%). We also identified microRNA profiles to subclassify ampullary adenocarcinomas into pancreatobiliary or intestinal type. In conclusion, we found that combinations of two microRNAs could roughly separate neoplastic from non-neoplastic samples. A diagnostic 19 microRNA classifier was constructed which without micro-dissection could discriminate pancreatic and ampullary adenocarcinomas from chronic pancreatitis and normal pancreas with high sensitivity and accuracy. Ongoing prospective studies will evaluate if these microRNA profiles are useful on fine-needle biopsies for early diagnosis of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-492"}
{"PMID":24216611,"Year":2014,"Title":"MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX.","Abstract":"The poor prognosis of invasive ductal adenocarcinoma of the pancreas is mainly due to its resistance against therapeutic agents. The molecular mechanism by which morbidity enhances cell survival has been extensively studied, but radical improvements in the therapeutic strategy have not yet been achieved. Recent reports have indicated the substantial contribution of miRNA in multiple cell functions by comprehensively targeting clusters of genes. We identified several miRNAs highly expressed in invasive ductal adenocarcinoma in our previous study, and clarified their contribution to the epithelial-mesenchymal transition. Among the differentially expressed miRNAs, miR-365 was highly expressed in invasive ductal adenocarcinoma, whose functional role has not been reported. In the current study, we found that miR-365 induced gemcitabine resistance in pancreatic cancer cells. MiR-365 directly targeted adaptor protein Src Homology 2 Domain Containing 1 (SHC1) and apoptosis-promoting protein BAX. The siRNA-based knockdown of SHC1 and BAX increased gemcitabine resistance, indicating the miR-365/SHC1/BAX axis influences the survival of pancreatic cancer cells. In addition, miR-365 up-regulated cancer-promoting molecules such as Inhibitor of DNA binding 2 and S100P, suggesting the existence of cross-talk with other cancer-promoting signals. MiR-365 could exert orchestrated effects on pancreatic cancer cell survival.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-365"}
{"PMID":22504911,"Year":2012,"Title":"Differential signature of fecal microRNAs in patients with pancreatic cancer.","Abstract":"The potential value of microRNAs as new biomarkers for pancreatic cancer (PCa) screening was explored in this study. Fecal microRNAs from stool samples obtained from 29 PCa patients, 22 chronic pancreatitis (CP) patients and 13 normal individuals were extracted, and 7 microRNAs (miR-16, miR-21, miR-155, miR-181a, miR-181b, miR-196a and miR-210) were detected. miR-181b and miR-210 discriminated PCa from normal individuals with receiver operating characteristic (ROC) curves and area under curve (AUC-ROC) of 0.745 and 0.772, respectively. There was a significant correlation between miR196a and the maximum tumor diameter (Spearman r = 0.516, P = 0.041). These findings suggest that fecal microRNAs such as miR-181b and miR-210 may have potential to be used as new biomarkers for PCa screening.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-181"}
{"PMID":19818597,"Year":2009,"Title":"MiRNA-29a regulates the expression of numerous proteins and reduces the invasiveness and proliferation of human carcinoma cell lines.","Abstract":"In this study we have identified a functional role for miR-29a in cancer cell invasion and proliferation. MiRNA expression profiling of human NSCLC cell lines indicated that miR-29a levels were reduced in more invasive cell lines. Exogenous overexpression of miR-29a in both lung and pancreatic cancer cell lines resulted in a significant reduction in the invasion phenotype, as well as in proliferation. 2D DIGE proteomic profiling of cells transfected with pre-miR-29a or anti-miR-29a resulted in the identification of over 100 differentially regulated proteins. The fold change of protein expression was generally modest--in the range 1.2-1.7-fold. Only 14 were predicted computationally to have miR-29a seed sequences in their 3' UTR region. Subsequent studies using siRNA to knock down several candidate proteins from the 2D DIGE experiment identified RAN (a member of the RAS oncogene family) which significantly reduced the invasive capability of a model lung cancer cell line. We conclude that miR-29a has a significant anti-invasive and anti-proliferative effect on lung cancer cells in vitro and functions as an anti-oncomir. This function is likely mediated through the post-transcriptional fine tuning of the cellular levels of several proteins, both directly and indirectly, and in particular we provide some evidence that RAN represents one of these.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-29"}
{"PMID":26919246,"Year":2016,"Title":"Methylation-associated silencing of miR-200b facilitates human hepatocellular carcinoma progression by directly targeting BMI1.","Abstract":"This study aims to investigate the biological function of microRNA-200b and BMI1, predicted target of microRNA-200b in human hepatocellular carcinoma (HCC). MicroRNA-200b and BMI1 expression in HCC tissues were evaluated by qPCR. A luciferase reporter assay was used to validate BMI1 as a direct target of microRNA-200b. The effect of microRNA-200b on HCC progression was studied in vitro and in vivo. Methylation specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to detect the methylation status of the microRNA-200b promoter. Significant downregulation of microRNA-200b was observed in 83.3% of HCC tissues. By contrast, BMI1 was significantly overexpressed in 66.7% of HCC tissues. The results of the luciferase assay confirmed BMI1 as a direct target gene of microRNA-200b. Forced expression of microRNA-200b in HCC cells dramatically repressed proliferation, colony formation, cell cycle progression, and invasion. Moreover, microRNA-200b synergized with 5-fluorouracil to induce apoptosis in vitro and suppressed tumorigenicity in vivo. In addition, MSP analysis and BSP revealed that CpG sites in the promoter region of microRNA-200b were extensively methylated in HCC, with concomitant downregulation of microRNA-200b expression. Furthermore, microRNA-200b was activated in HCC cells after treatment with 5-azacytidine, whereas BMI1 expression was clearly downregulated. Our results indicate that microRNA-200b is partially silenced by DNA hypermethylation and that it can repress tumor progression by directly targeting BMI1 in HCC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-200"}
{"PMID":26499892,"Year":2015,"Title":"Small nucleolar RNA U91 is a new internal control for accurate microRNAs quantification in pancreatic cancer.","Abstract":"BACKGROUND: RT-qPCR quantification of miRNAs expression may play an essential role in pancreatic ductal adenocarcinoma (PDAC) diagnostics. RT-qPCR-based experiments require endogenous controls for the result normalization and reliability. However, expression instability of reference genes in tumors may introduce bias when determining miRNA levels. METHODS: We investigated expression of 6 miRNAs, isolated from FFPE samples of pancreatic adenocarcinomas. Four internal controls were utilized for RT-qPCR result normalization: artificial miR-39 from C. elegans, U6 snRNA, miR-16 and snoRNA U91. RESULTS: We found miR-21, miR-155 or miR-217 expression values in tumors may differ up to several times, depending on selected internal controls. Moreover, different internal controls can produce controversial results for miR-96, miR-148a or miR-196a quantification. Also, expression of our endogenous controls varied significantly in tumors. U6 demonstrated variation from -1.03 to 8.12-fold, miR-16 from -2.94 up to 7.38-fold and the U91 from -3.05 to 4.36-fold respectively. On the other hand, the most stable gene, determined by NormFinder algorithm, was U91. Each miRNA normalized relatively to the spike or U91, demonstrated similar expression values. Thus, statistically significant and insignificant differences between tumors and normal tissues for miRNAs were equal for the spike and the U91. Also, the differences between the spike and U91 were statistically insignificant for all of miRs except miR-217. Among three endogenous controls, U91 had the lowest average expression values and standard deviation in cancer tissues. CONCLUSIONS: We recommend U91 as a new normalizer for miRNA quantification in PDACs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-148"}
{"PMID":22303361,"Year":2011,"Title":"MicroRNAs in Hepatobiliary and Pancreatic Cancers.","Abstract":"MicroRNAs (miRNAs) are small non-coding RNAs that function as endogenous silencers of numerous target genes. Hundreds of miRNAs have been identified in the human genome. miRNAs are expressed in a tissue-specific manner and play important roles in cell proliferation, apoptosis, and differentiation. Aberrant expression of miRNAs may also contribute to the development and progression of human hepatobiliary and pancreatic cancers. Recent studies have shown that some miRNAs play roles as tumor suppressors or oncogenes in hepatobiliary and pancreatic cancers. miR-122, let-7 family, and miR-101 are down-regulated in hepatocellular carcinoma (HCC), suggesting that it is a potential tumor suppressor of HCC. miR-221 and miR-222 are up-regulated in HCC and may act as oncogenic miRNAs in hepatocarcinogenesis. miRNA expression profiling may be a powerful clinical tool for diagnosis and regulation of miRNA expression could be a novel therapeutic strategy for hepatobiliary and pancreatic cancers. In this review, we summarize current knowledge about the roles of important tumor suppressor microRNAs and oncogenic microRNAs in hepatobiliary and pancreatic cancers.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"let-7"}
{"PMID":28498896,"Year":2017,"Title":"Inhibition of PRDM14 expression in pancreatic cancer suppresses cancer stem-like properties and liver metastasis in mice.","Abstract":"Pancreatic cancer is one of the most lethal types of cancer, with aggressive properties characterized by metastasis, recurrence and drug resistance. Cancer stem cells are considered to be responsible for these properties. PRDM14, a transcriptional regulator that maintains pluripotency in embryonic stem cells, is overexpressed in some cancers. Here, we assessed PRDM14 expression and the effects of PRDM14 knockdown on cancer stem-like phenotypes in pancreatic cancer. We observed that PRDM14 protein was overexpressed in pancreatic cancer tissues compared with normal pancreatic tissues. Using lentiviral shRNA-transduced pancreatic cancer cells, we found that PRDM14 knockdown decreased sphere formation, number of side population and cell surface marker-positive cells and subcutaneous xenograft tumors and liver metastasis in mice. This was accompanied by upregulation of some microRNAs (miRNAs), including miR-125a-3p. miR-125a-3p, a tumor suppressor that is down-regulated in pancreatic cancer, has been suggested to regulate the expression of the Src-family kinase, Fyn. In PRDM14-knockdown cells, Fyn was expressed at lower levels and downstream proteins were less activated. These changes were considered to cause suppression of the above cancer phenotypes. In addition, we used small interfering RNA (siRNA)-based therapy targeting PRDM14 in a mouse model of liver metastasis induced using MIA-PaCa2 cells, and this treatment significantly decreased metastasis and in vitro migration. Taken together, these results suggest that targeting the overexpression of PRDM14 suppresses cancer stem-like phenotypes, including liver metastasis, via miRNA regulation and siRNA-based therapy targeting it shows promise as a treatment for patients with pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-125"}
{"PMID":30225540,"Year":2018,"Title":"Circulating microRNA-99 family as liquid biopsy marker in pancreatic adenocarcinoma.","Abstract":"PURPOSE: Recently, we identified the microRNA-99 family as unfavorable prognostic factor in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study is to evaluate its value as circulating biomarker for PDAC. METHODS: Tissue and corresponding preoperative blood samples of 181 patients with PDAC UICC Stages I-IV (n = 90), intraductal papillary mucinous neoplasm (IPMN, n = 11), chronic pancreatitis (n = 40), pancreatic cystadenoma (n = 20), and age-matched healthy blood serum controls (n = 20) were collected between 2014 and 2017 prospectively. Expression of microRNA-21 as confirmatory marker and the microRNA-99 family, consisting of microRNA-99a, -99b, and -100, was analyzed by qRT-PCR. Target analysis of insulin-like growth factor 1 receptor (IGF1R) was performed using tissue array immunohistochemistry and Western blotting. RESULTS: Expression of microRNA-99 family members was significantly increased in macrodissected tumor tissue and corresponding blood serum samples (p < 0.05) of patients with PDAC of all stages. Correspondingly, its target protein IGF1R was upregulated (p < 0.001) in carcinoma tissue. Circulating and tissue-related microRNA-100 could well discriminate PDAC from healthy samples with area under the receiver operating characteristic (ROC) curve (AUC) values of 0.81 and 0.85, respectively. Low expression of circulating microRNA-100 was associated with significantly improved overall survival (p = 0.004) and recurrence-free survival (p = 0.03) in multivariate analyses. Circulating microRNA-21 was overexpressed in PDAC with fair discrimination between PDAC and healthy controls (AUC = 0.71) and decreased overall survival (p = 0.046) and recurrence-free survival (p = 0.03) in PDAC patients. CONCLUSIONS: Multivariate survival and ROC analyses identified circulating microRNA-100 as potential diagnostic and prognostic marker in PDAC patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-100"}
{"PMID":19569050,"Year":2010,"Title":"EP300--a miRNA-regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas.","Abstract":"Genetic and epigenetic alterations during development of pancreatic ductal adenocarcinomas (PDACs) are well known. This study investigates genetic and epigenetic data together with tumor biology to find specific alterations responsible for metastasis formation. Using 16 human PDAC cell lines in a murine orthotopic PDAC model, local infiltration and metastatic spread were assessed by standardized dissemination scores. The cell lines were further classified into 3 hierarchical groups according to their metastatic potential. Their mRNA and microRNA (miRNA) expression was profiled via mRNA-microarray as well as Taqman Low Density Array, and validated by single quantitative RT-PCR and Western blotting. In the highly metastatic group, a significant induction of EP300 targeting miRNAs miR-194 (fold change: 26.88), miR-200b (fold change: 61.65), miR-200c (fold change: 19.44) and miR-429 (fold change: 21.67) (p < 0.05) was detected. Corresponding to this, decreased expression of EP300 mRNA (p < 0.0001) and protein (p < 0.05) were detected in the highly metastatic PDAC cell lines with liver metastases compared to the nonmetastatic or marginally metastatic cell lines, while no correlation with local tumor growth was found. In conclusion, epigenetic alterations with upregulated EP300 targeting miRNAs miR-194, miR-200b, miR-200c and miR-429 are related to reduced EP300 mRNA and protein in PDAC. These results demonstrate that miRNAs might be able to modulate the expression of metastasis-specific suppressor genes and metastatic behavior in PDAC, suggesting diagnostic and therapeutic opportunities for EP300 and its targeting miRNAs in PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-429"}
{"PMID":23149065,"Year":2013,"Title":"Multi-target lentivirus specific to hepatocellular carcinoma: in vitro and in vivo studies.","Abstract":"BACKGROUND & AIMS: We aimed at investigating the effects of the targeted transduction of the Wtp53-pPRIME-miR30-shRNA gene into liver cancer cells, under the mediation of anti-alpha fetoprotein scFv-directed lentivirus, and the inhibitory effect of this system on liver cancer cells. METHODS: The result of infection was observed by fluorescence microscopy. Polymerase chain reaction and Western blotting were used to demonstrate the successful transduction and transcription of the Wtp53-pPRIME-miR30-shRNA-IGF1R gene. Cell growth was observed via the Cell-Counting Kit-8 Method, and cell apoptosis was detected by terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling. To observe further the effects of AFP-Wtp53-pPRIME-miR30-shRNA-IGF1R therapy in animals, models of BALB-C nude mice bearing subcutaneous human hepatocellular carcinoma were established. The influence of the growth of subcutaneously transplanted tumor, expression of Wtp53 protein, apoptosis, and microvessel formation on the overall level of AFP-Wtp53 pPRIME-miR30-shRNA-IGF1R were also evaluated. RESULTS: Recombinant lentivirus was successfully constructed, and its functional plaque-forming unit titer was determined as 4.58 x 10(9)plaque-forming units/ml. A positive strand was detected by polymerase chain reaction and Western blotting. Lentiviral construction worked effectively in AFP-positive liver cancer cells. In vitro and in vivo experiments showed that the recombinant lentivirus was more efficacious in inhibiting the proliferation of Hep3B cells. CONCLUSIONS: The Wtp53-pPRIME-miR30-shRNA gene can be subjected to targeted transduction into liver cancer cells under the mediation of anti-alpha fetoprotein scFv-directed lentivirus. The Wtp53-pPRIME-miR30-shRNA system has targeting ability and lethal effects on liver cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-30"}
{"PMID":30021866,"Year":2019,"Title":"Evaluating gastroenteropancreatic neuroendocrine tumors through microRNA sequencing.","Abstract":"Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) can be challenging to evaluate histologically. MicroRNAs (miRNAs) are small RNA molecules that often are excellent biomarkers due to their abundance, cell-type and disease stage specificity and stability. To evaluate miRNAs as adjunct tissue markers for classifying and grading well-differentiated GEP-NETs, we generated and compared miRNA expression profiles from four pathological types of GEP-NETs. Using quantitative barcoded small RNA sequencing and state-of-the-art sequence annotation, we generated comprehensive miRNA expression profiles from archived pancreatic, ileal, appendiceal and rectal NETs. Following data preprocessing, we randomly assigned sample profiles to discovery (80%) and validation (20%) sets prior to data mining using machine-learning techniques. High expression analyses indicated that miR-375 was the most abundant individual miRNA and miRNA cistron in all samples. Leveraging prior knowledge that GEP-NET behavior is influenced by embryonic derivation, we developed a dual-layer hierarchical classifier for differentiating GEP-NET types. In the first layer, our classifier discriminated midgut (ileum, appendix) from non-midgut (rectum, pancreas) NETs based on miR-615 and -92b expression. In the second layer, our classifier discriminated ileal from appendiceal NETs based on miR-125b, -192 and -149 expression, and rectal from pancreatic NETs based on miR-429 and -487b expression. Our classifier achieved overall accuracies of 98.5% and 94.4% in discovery and validation sets, respectively. We also found provisional evidence that low- and intermediate-grade pancreatic NETs can be discriminated based on miR-328 expression. GEP-NETs can be reliably classified and potentially graded using a limited panel of miRNA markers, complementing morphological and immunohistochemistry-based approaches to histologic evaluation.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-149"}
{"PMID":27080237,"Year":2016,"Title":"Stratification of Digestive Cancers with Different Pathological Features and Survival Outcomes by MicroRNA Expression.","Abstract":"MicroRNAs (miRNAs) are aberrantly expressed in virtually all cancer types, including digestive cancers. Herein, we aggregated and systematically analyzed miRNA expression profiles of 1765 tumor samples, including esophageal, gastric, liver, pancreatic, colon and rectal cancers, obtained through small RNA sequencing by The Cancer Genome Atlas. We found that digestive cancers of different tissue origins could be differentiated according to their miRNA expression profiles. In particular, esophageal squamous cell carcinoma and esophageal adenocarcinoma exhibited distinct miRNA expression patterns. Thirteen (e.g. miR-135b, miR-182) and sixteen (e.g. miR-139, miR-133a-1, miR-490) miRNAs were commonly upregulated and downregulated in more than four cancer types, respectively. Pertinent to pathological features, low miR-181d expression was associated with microsatellite instability in colon and gastric cancers whereas low miR-106a expression was associated with hepatitis B virus infection in hepatocellular carcinoma. Progression in colon cancer could also be predicted by low let-7f-2 and high miR-106a expression. Molecular subtypes with distinct prognostic outcomes independent of tumor-node-metastasis staging were identified in hepatocellular carcinoma and colon cancer. In total, 4 novel and 6 reported associations between specific miRNAs and patients' survival were identified. Collectively, novel miRNA markers were identified to stratify digestive cancers with different pathological features and survival outcomes.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-106"}
{"PMID":24734907,"Year":2014,"Title":"Differentially expressed miRNAs in cancer-stem-like cells: markers for tumor cell aggressiveness of pancreatic cancer.","Abstract":"Pancreatic cancer (PC) is one of the most deadly cancers. The higher mortality is in part due to treatment resistance and early onset of metastasis. The existence of cancer-stem-like cells (CSLCs) has been widely accepted to be responsible for tumor aggressiveness in PC. Emerging evidence suggests that CSLCs have the capacity for increased cell growth, cell migration/invasion, metastasis, and treatment resistance, which leads to poor clinical outcome. However, the molecular role of CSLCs in tumor development and progression is poorly understood. Therefore, mechanistic understanding, and targeted killing of CSLCs may provide a newer therapeutic strategy for the treatment of PC. It has been well accepted that microRNAs (miRNAs) play critical roles during tumor development and progression through deregulation of multiple genes. Moreover, deregulated expression of miRNAs may also play a key role in the regulation of CSLC characteristics and functions. Here we show that isolated CD44(+)/CD133(+)/EpCAM(+) cells (triple-marker-positive cells) from human PC cell lines, MiaPaCa-2 and L3.6pl cells, display aggressive characteristics, such as increased cell growth, clonogenicity, cell migration, and self-renewal capacity, which is consistent with overexpression of CSLC signatures/markers. We also found deregulated expression of over 400 miRNAs, including let-7, miR-30, miR-125b, and miR-335, in CSLCs. As a proof-of-concept, knockdown of miR-125b resulted in the inhibition of tumor cell aggressiveness of CSLCs (triple-marker-positive cells), consistent with the downregulation of CD44, EpCAM, EZH2, and snail. These results clearly suggest the importance of miRNAs in the regulation of CSLC characteristics, and may serve as novel targets for therapy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-335"}
{"PMID":30389902,"Year":2018,"Title":"MiR-15a/miR-16-1 expression inversely correlates with cyclin D1 levels in Men1 pituitary NETs.","Abstract":"Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by the combined occurrence of parathyroid, pituitary and pancreatic islet tumours, and is due to mutations of the MEN1 gene, which encodes the tumour suppressor protein menin. Menin has multiple roles in genome stability, transcription, cell division and proliferation, but its mechanistic roles in tumourigenesis remain to be fully elucidated. MicroRNAs (miRNA) are non-coding single stranded RNAs that post-transcriptionally regulate gene expression and have been associated with tumour development, although the contribution of miRNAs to MEN1-associated tumourigenesis and their relationship with menin expression are not fully understood. Alterations in miRNA expression, including downregulation of three putative 'tumour suppressor' miRNAs, miR-15a, miR-16-1 and let-7a, have been reported in several tumour types including non-MEN1 pituitary adenomas. We have therefore investigated the expression of miR-15a, miR-16-1 and let-7a in pituitary tumours that developed after 12 months of age in female mice with heterozygous knock out of the Men1 gene (Men1+/- mice). The miRNAs miR-15a, miR-16-1 and let-7a were significantly downregulated in pituitary tumours (by 2.3-fold, p<0.05; 2.1-fold p<0.01 and 1.6-fold p<0.05, respectively) of Men1+/- mice, compared to normal wild type pituitaries. MiR-15a and miR-16-1 expression inversely correlated with expression of cyclin D1, a known pro-tumourigenic target of these miRNAs, and knock down of menin in a human cancer cell line (HeLa), and AtT20 mouse pituitary cell line resulted in significantly decreased expression of miR-15a (p<0.05), indicating that the decrease in miR-15a may be a direct result of lost menin expression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-15"}
{"PMID":24778027,"Year":2014,"Title":"Global microRNA profiling of pancreatic neuroendocrine neoplasias.","Abstract":"BACKGROUND: Pancreatic neuroendocrine neoplasms (pNEN) are rare tumors with a poor prognosis. Although increasing data have accumulated on the molecular pathology of pNEN, very scarce data exist on microRNAs in pNEN and no data are published on microRNAs as potential biomarkers of pNEN in serum. This study aimed to identify microRNA signatures of pNEN in tissue and serum. MATERIALS AND METHODS: We included tissue samples from 37 patients with pNEN, 9 patients with non-neoplastic pancreatic pathology, seven samples of micro-dissected pancreatic islets and serum samples of 27 patients with pNEN, as well as of 15 healthy volunteers. MicroRNA expression profiles were established using real-time quantitative Polymerase Chain reaction (PCR) for 754 microRNAs. RESULTS: MicroRNA signatures differed between pNEN, pancreatic islets and total pancreas, with virtually no overlap between the groups of de-regulated microRNAs. Expression of miR-642 correlated with Ki67 (MiB1) score and miR-210 correlated with metastatic disease. When comparing microRNA levels in serum from patients with pNEN and healthy volunteers, 13 microRNAs were more abundant in the serum of patients. MiR-193b was also up-regulated in pNEN tissue when compared to pancreatic islets and remained significantly increased in serum even when corrected for multiple testing. CONCLUSION: Evaluation of microRNAs appears to be promising in the assessment of pNEN. In particular, miR-193b, which is also increased in serum, may be a potential new biomarker of pNEN.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-642"}
{"PMID":21329664,"Year":2011,"Title":"miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor.","Abstract":"Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR-212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target the retinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR-132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G(2)/M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the beta2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over-expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The beta2 adrenergic pathway may play an important role in this novel mechanism.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-132"}
{"PMID":27690301,"Year":2016,"Title":"MiR-128 reverses the gefitinib resistance of the lung cancer stem cells by inhibiting the c-met/PI3K/AKT pathway.","Abstract":"Gefitinib is a first line anti-tumor drug used for the treatment of patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, the drug resistance to gefitinib limits its clinical application. Here, we observed the CSCs of PC9 are obviously resistant to gefitinib compared with the non-CSCs. Furthermore, we found the gefitinib failed to suppress the PI3K/AKT pathway in the PC9-CSCs. Mechanically, we showed significant down-regulation of miR-128 in the PC9-CSCs compared with the non-CSCs. Overexpression of miR-128 significantly increased the sensitivity of PC9-CSCs to gefitinib-induced apoptosis. In addition, the gene of c-met was proved to be directly inhibited by miR-128. Enforced expression of c-met could \"rescue\" the miR-128 promoted apoptosis and cleavage of caspases in PC9-CSCs treated with gefitinib. Thus, these results indicate that the miR-128/c-met pathway enhances the gefitinib sensitivity of the lung cancer stem cells by suppressing the PI3K/AKT pathway.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-128"}
{"PMID":29408481,"Year":2018,"Title":"MiR-7-5p functions as a tumor suppressor by targeting SOX18 in pancreatic ductal adenocarcinoma.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Recently, many kinds of microRNAs (miRNAs) have been found to play a significant role in development of PDAC. However, there is no investigation about expression and function of miR-7-5p in PDAC. In this study, we found that miR-7-5p was down-regulated in PDAC tissues and its low expression level indicated a poor survival rate for PDAC patients. By bioinformatic analysis, we found that miR-7-5p targeted SOX18, and there was a negative correlation between them in PDAC tissues. Then luciferase reporter and western blot assays were used to verify the binding of miR-7-5p on SOX18 3'UTR. Cell function assays demonstrated that miR-7-5p inhibited proliferation, migration and invasion of PANC-1cells by targeting SOX18. The nude mouse tumorigenicity assay further proved that miR-7-5p targeted SOX18 to inhibit pancreatic cancer growth in vivo. In order to further understand the mechanism, we applied a transcription factor prediction tool to explore the underlying targets that transcripted by SOX18, and the result indicated that SOX18 was a transcription factor for gp130 (a subunit of IL-6 receptor), and ChIP assays was performed to prove this prediction. Furthermore, we detected the suppression of gp130/JAK2/STAT3 signaling pathway after silencing SOX18 in PANC-1cells, which demonstrated the transcriptional activation role of SOX18 on gp130. Thus, our present study revealed that miR-7-5p targeted SOX18 to inhibit gp130/JAK2/STAT3 signaling pathway to exert its suppressing role in PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-7"}
{"PMID":29141872,"Year":2018,"Title":"miR-23a acts as an oncogene in pancreatic carcinoma by targeting FOXP2.","Abstract":"MicroRNAs have been reported to play an important role in tumor development and progression by targeting oncogenes and tumor suppressors. miR-23a has been described as significantly upregulated in multiple cancers and involved in tumorigenesis. The aim of this study was to evaluate the potential roles of miR-23a in pancreatic ductal adenocarcinoma (PDAC). We found that miR-23a level was significantly increased in tissues of PDAC compared with that in the control by real-time PCR. FOXP2 expression was downregulated and inversely correlated with miR-23a. miR-23a directly targeted the 3'-untranslated region of FOXP2 mRNA and repressed its expression. Mechanistically, enhancement of miR-23a by transfection with mimics in Aspc-1 cells significantly promoted cell proliferation and invasion, while miR-23a inhibitors transfection in SW1990 cells induced an inhibitory effect. Moreover, restoration of FOXP2 impaired the pro-proliferation and proinvasion effects of miR-23a, indicating FOXP2 is a direct mediator of miR-23a functions. In conclusion, our findings suggest a novel miR-23a/FOXP2 link contributing to PDAC development and invasion. It may be a potential diagnostic and therapeutic target for PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-23"}
{"PMID":29050264,"Year":2017,"Title":"The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster.","Abstract":"We analysed the RNA sequence-based microRNA (miRNA) signature of pancreatic ductal adenocarcinoma (PDAC). Aberrantly expressed miRNAs were successfully identified in this signature. Using the PDAC signature, we focused on 4 clustered miRNAs, miR-216a-5p, miR-216a-3p, miR-216b-5p and miR-216b-3p on human chromosome 2p16.1. All members of the miR-216 cluster were significantly reduced in PDAC specimens. Ectopic expression of these miRNAs suppressed cancer cell aggressiveness, suggesting miR-216 cluster as anti-tumour miRNAs in PDAC cells. The impact of miR-216b-3p (passenger strand of pre-miR-216b) on cancer cells is still ambiguous. Forkhead box Q1 (FOXQ1) was directly regulated by miR-216b-3p and overexpression of FOXQ1 was confirmed in clinical specimens. High expression of FOXQ1 predicted a shorter survival of patients with PDAC by Kaplan-Meier analysis. Loss-of-function assays showed that cancer cell migration and invasion activities were significantly reduced by siFOXQ1 transfectants. We investigated pathways downstream from FOXQ1 by using genome-wide gene expression analysis. Identification of the miR-216-3p/FOXQ1-mediated network in PDAC should enhance understanding of PDAC aggressiveness at the molecular level.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-216"}
{"PMID":29111329,"Year":2018,"Title":"Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells.","Abstract":"Pancreatic cancer cells (PCCs) interact with pancreatic stellate cells (PSCs), which play a pivotal role in pancreatic fibrogenesis, to develop the cancer-conditioned tumor microenvironment. Exosomes are membrane-enclosed nanovesicles, and have been increasingly recognized as important mediators of cell-to-cell communications. The aim of this study was to clarify the effects of PCC-derived exosomes on cell functions in PSCs. Exosomes were isolated from the conditioned medium of Panc-1 and SUIT-2 PCCs. Human primary PSCs were treated with PCC-derived exosomes. PCC-derived exosomes stimulated the proliferation, migration, activation of ERK and Akt, the mRNA expression of alpha-smooth muscle actin (ACTA2) and fibrosis-related genes, and procollagen type I C-peptide production in PSCs. Ingenuity pathway analysis of the microarray data identified transforming growth factor beta1 and tumor necrosis factor as top upstream regulators. PCCs increased the expression of miR-1246 and miR-1290, abundantly contained in PCC-derived exosomes, in PSCs. Overexpression of miR-1290 induced the expression of ACTA2 and fibrosis-related genes in PSCs. In conclusion, PCC-derived exosomes stimulate activation and profibrogenic activities in PSCs. Exosome-mediated interactions between PSCs and PCCs might play a role in the development of the tumor microenvironment.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1290"}
{"PMID":31311829,"Year":2019,"Title":"Identification of novel genes associated with a poor prognosis in pancreatic ductal adenocarcinoma via a bioinformatics analysis.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a class of the commonest malignant carcinomas. The present study aimed to elucidate the potential biomarker and prognostic targets in PDAC. The array data of GSE41368, GSE43795, GSE55643, and GSE41369 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) and differentially expressed microRNAs (DEmiRNAs) in PDAC were obtained by using GEO2R, and overlapped DEGs were acquired with Venn Diagrams. Functional enrichment analysis of overlapped DEGs and DEmiRNAs was conducted with Metascape and FunRich, respectively. The protein-protein interaction (PPI) network of overlapped DEGs was constructed by STRING and visualized with Cytoscape. Overall survival (OS) of DEmiRNAs and hub genes were investigated by Kaplan-Meier (KM) plotter (KM plotter). Transcriptional data and correlation analyses among hub genes were verified through GEPIA and Human Protein Atlas (HPA). Additionally, miRNA targets were searched using miRTarBase, then miRNA-DEG regulatory network was visualized with Cytoscape. A total of 32 DEmiRNAs and 150 overlapped DEGs were identified, and Metascape showed that DEGs were significantly enriched in cellular chemical homeostasis and pathways in cancer, while DEmiRNAs were mainly enriched in signal transduction and Glypican pathway. Moreover, seven hub genes with a high degree, namely, V-myc avian myelocytomatosis viral oncogene homolog (MYC), solute carrier family 2 member 1 (SLC2A1), PKM, plasminogen activator, urokinase (PLAU), peroxisome proliferator activated receptor gamma (PPARG), MET proto-oncogene, receptor tyrosine kinase (MET), and integrin subunit alpha 3 (ITGA3), were identified and found to be up-regulated between PDAC and normal tissues. miR-135b, miR-221, miR-21, miR-27a, miR-199b-5p, miR-143, miR-196a, miR-655, miR-455-3p, miR-744 and hub genes predicted poor OS of PDAC. An integrative bioinformatics analysis identified several hub genes that may serve as potential biomarkers or targets for early diagnosis and precision target treatment of PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-744"}
{"PMID":26677401,"Year":2015,"Title":"MicroRNA profiling of primary pulmonary enteric adenocarcinoma in members from the same family reveals some similarities to pancreatic adenocarcinoma-a step towards personalized therapy.","Abstract":"BACKGROUND: Primary pulmonary enteric adenocarcinoma (PEAC) is defined as a pulmonary adenocarcinoma with a predominant component of intestinal differentiation and tumor cells positive for at least one intestinal marker. The aim of the present study was the molecular and histological characterization of a PEAC from a patient with two other family members affected by similar lung tumors, which has never been reported before. FINDINGS: We evaluated the molecular characteristics of the proband's PEAC by using a previously validated 47-microRNA (miRNA) cancer-specific array and a predictive method to estimate tissue-of-origin probabilities. Immunohistochemical (IHC) staining for thyroid transcription factor (TTF-1), napsin A, caudal-related homeobox 2 (CDX2), cytokeratins, and mucins, as well as mutational analyses for epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK) were performed on formalin-fixed, paraffin-embedded (FFPE) tissues. The occurrence of PEAC in two family members was associated with similar clinicopathological features (age at diagnosis, smoking habit, tumor localization, multiple colonic polyps), histologic findings (TTF-1 negativity and CDX2 positivity), and genetic findings (KRAS (Gly12Asp) mutation, but no EGFR/ALK aberrations). miRNA profiling revealed similarities with non-small cell lung cancer (NSCLC; 75.98 %) and some overlap with pancreatic ductal adenocarcinoma (PDAC; 23.34 %), but not with colorectal cancer (CRC; less than 0.5 %). Notably, these PEACs share key PDAC-associated miRNAs associated with tumor aggressiveness (miR-31*/-126*/-506/-508-3p/-514). CONCLUSIONS: We describe for the first time PEAC in members from the same family, associated with similar clinical and genetic features. miRNA profiling of the PEAC resembled a NSCLC signature, with partial overlap to a PDAC pattern. This could explain its aggressive behavior and therefore help to guide future tailored-therapeutic approaches.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-31"}
{"PMID":24892299,"Year":2014,"Title":"Expression of microRNA-15b and the glycosyltransferase GCNT3 correlates with antitumor efficacy of Rosemary diterpenes in colon and pancreatic cancer.","Abstract":"Colorectal and pancreatic cancers remain important contributors to cancer mortality burden and, therefore, new therapeutic approaches are urgently needed. Rosemary (Rosmarinus officinalis L.) extracts and its components have been reported as natural potent antiproliferative agents against cancer cells. However, to potentially apply rosemary as a complementary approach for cancer therapy, additional information regarding the most effective composition, its antitumor effect in vivo and its main molecular mediators is still needed. In this work, five carnosic acid-rich supercritical rosemary extracts with different chemical compositions have been assayed for their antitumor activity both in vivo (in nude mice) and in vitro against colon and pancreatic cancer cells. We found that the antitumor effect of carnosic acid together with carnosol was higher than the sum of their effects separately, which supports the use of the rosemary extract as a whole. In addition, gene and microRNA expression analyses have been performed to ascertain its antitumor mechanism, revealing that up-regulation of the metabolic-related gene GCNT3 and down-regulation of its potential epigenetic modulator miR-15b correlate with the antitumor effect of rosemary. Moreover, plasmatic miR-15b down-regulation was detected after in vivo treatment with rosemary. Our results support the use of carnosic acid-rich rosemary extract as a complementary approach in colon and pancreatic cancer and indicate that GCNT3 expression may be involved in its antitumor mechanism and that miR-15b might be used as a non-invasive biomarker to monitor rosemary anticancer effect.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-15"}
{"PMID":26662405,"Year":2015,"Title":"MicroRNA-215 functions as a tumor suppressor and directly targets ZEB2 in human pancreatic cancer.","Abstract":"It has been shown that microRNA-215 (miR-215) is dysregulated in several human malignancies, and this correlates with tumor progression. However, its expression and function in pancreatic cancer is still unclear. The aim of this study was to explore the effects of miR-215 on pancreatic cancer formation and progression. Using quantitative RT-PCR, we detected miR-215 expression in pancreatic cancer cell lines and primary tumor tissues. The association of miR-215 expression with clinicopathological factors and prognosis was also analyzed. We then observed the effects of miR-215 on the biological behavior of pancreatic cancer cells. Lastly, the potential regulatory function of miR-215 on ZEB2 expression was investigated. miR-215 expression levels were significantly downregulated in pancreatic cancer samples and cell lines. Decreased miR-215 expression was significantly associated with large tumor size, advanced TNM stage, lymph node metastasis, vessel invasion, and lower overall survival. Multivariate regression analysis corroborated that downregulation of miR-215 was an independent unfavorable prognostic factor. Overexpression of miR-215 inhibited pancreatic cancer cell proliferation, invasion, and migration; promoted cell apoptosis in vitro; and suppressed tumorigenicity in vivo. Further, ZEB2 was confirmed as a direct target of miR-215 by using a luciferase reporter assay. These findings indicate that miR-215 may act as a tumor suppressor in pancreatic cancer cells, and could serve as a novel therapeutic target for miR-based therapy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-215"}
{"PMID":26505678,"Year":2015,"Title":"Plasma microRNA profiles: identification of miR-744 as a novel diagnostic and prognostic biomarker in pancreatic cancer.","Abstract":"BACKGROUND: This study aims to explore novel microRNAs in plasma for screening cancer and predicting clinical outcomes in pancreatic cancer (PCa) patients using a microRNA array-based approach. METHODS: We used the Toray 3D-Gene microRNA array-based approach to compare plasma levels between PCa patients and healthy volunteers. RESULTS: (1) Six oncogenic microRNAs (miR-615-5p, -744, -575, -557, -675, and -550a) with high expression in plasma were selected. (2) By quantitative RT-PCR using plasma samples from 94 PCa patients and 68 healthy volunteers, a significantly higher level of plasma miR-744 in PCa patients than in healthy volunteers was validated in small-scale analysis (P=0.0038), two independent cohort analyses, and large-scale analysis (P<0.0001, AUC 0.8307). (3) miR-744 expression was significantly higher in PCa tissues (P=0.0069) and PCa cell lines (P=0.0074) than in normal tissues and fibroblasts, respectively. Preoperative plasma level of miR-744 was significantly reduced in postoperative samples (P=0.0063). (4) A high level of plasma miR-744, which was correlated with lymph node metastasis (P=0.0407) and recurrences (P=0.0376), was an independent poor prognostic factor of PCa patients after pancreatectomy (P=0.0007, HR 21.2 (3.17-436)). Furthermore, a high level of plasma miR-744 contributed to poorer progression-free survival of non-operable PCa patients who underwent gemcitabine-based chemotherapy (P=0.0533). Overexpression of miR-744 in PCa cells induced significant chemoresistance to gemcitabine in vitro. CONCLUSIONS: Plasma miR-744 might be useful biomarker for screening PCa, monitoring, and predicting poor prognosis and chemoresistance in PCa patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-675"}
{"PMID":24449318,"Year":2014,"Title":"MicroRNA biomarkers in whole blood for detection of pancreatic cancer.","Abstract":"IMPORTANCE: Biomarkers for the early diagnosis of patients with pancreatic cancer are needed to improve prognosis. OBJECTIVES: To describe differences in microRNA expression in whole blood between patients with pancreatic cancer, chronic pancreatitis, and healthy participants and to identify panels of microRNAs for use in diagnosis of pancreatic cancer compared with the cancer antigen 19-9 (CA19-9). DESIGN, SETTING, AND PARTICIPANTS: A case-control study that included 409 patients with pancreatic cancer and 25 with chronic pancreatitis who had been included prospectively in the Danish BIOPAC (Biomarkers in Patients with Pancreatic Cancer) study (July 2008-October 2012) plus 312 blood donors as healthy participants. The microRNA expressions in pretreatment whole blood RNA samples were collected and analyzed in 3 randomly determined subcohorts: discovery cohort (143 patients with pancreatic cancer, 18 patients with chronic pancreatitis, and 69 healthy participants), training cohort (180 patients with pancreatic cancer, 1 patient with chronic pancreatitis, and 199 healthy participants), and validation cohort (86 patients with pancreatic cancer, 7 patients with chronic pancreatitis, and 44 healthy participants); 754 microRNAs were screened in the discovery cohort and 38 microRNAs in the training cohort and 13 microRNAs in the validation cohort. MAIN OUTCOMES AND MEASURES: Identification of microRNA panels (classifiers) for diagnosing pancreatic cancer. RESULTS: The discovery cohort demonstrated that 38 microRNAs in whole blood were significantly dysregulated in patients with pancreatic cancer compared with controls. These microRNAs were tested in the training cohort and 2 diagnostic panels were constructed comprising 4 microRNAs in index I (miR-145, miR-150, miR-223, miR-636) and 10 in index II (miR-26b, miR-34a, miR-122, miR-126*, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p). The test characteristics for the training cohort were index I area under the curve (AUC) of 0.86 (95% CI, 0.82-0.90), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.64 (95% CI, 0.57-0.71); index II AUC of 0.93 (95% CI, 0.90-0.96), sensitivity of 0.85 (95% CI, 0.79-0.90), and specificity of 0.85 (95% CI, 0.80-0.85); and CA19-9 AUC of 0.90 (95% CI, 0.87-0.94), sensitivity of 0.86 (95% CI, 0.80-0.90), and specificity of 0.99 (95% CI, 0.96-1.00). Performances were strengthened in the validation cohort by combining panels and CA19-9 (index I AUC of 0.94 [95% CI, 0.90-0.98] and index II AUC of 0.93 [95% CI, 0.89-0.97]). Compared with CA19-9 alone, the AUC for the combination of index I and CA19-9 was significantly higher (P = .01). The performance of the panels in patients with stage IA-IIB pancreatic cancer was index I AUC of 0.80 (95% CI, 0.73-0.87); index I and CA19-9 AUC of 0.83 (95% CI, 0.76-0.90); index II AUC of 0.91 (95% CI, 0.87-0.94); and index II and CA19-9 AUC of 0.91 (95% CI, 0.86-0.95). CONCLUSIONS AND RELEVANCE: This study identified 2 diagnostic panels based on microRNA expression in whole blood with the potential to distinguish patients with pancreatic cancer from healthy controls. Further research is necessary to understand whether these have clinical implications for early detection of pancreatic cancer and how much this information adds to serum CA19-9.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-26"}
{"PMID":26063036,"Year":2015,"Title":"miR-215 overexpression distinguishes ampullary carcinomas from pancreatic carcinomas.","Abstract":"Distinguishing ampullary carcinoma from pancreatic carcinoma is important because of their different prognoses. microRNAs are differentially expressed according to the tissue of origin. However, there is rare research on the differential diagnosis between the two types of cancers by microRNA in periampullary cancers. The present study was undertaken to compare microRNA profiles between ampullary and pancreatic carcinomas using microarrays. miR-215 was most significantly overexpressed in ampullary carcinomas; whereas the expressions of miR-134 and miR-214 were significantly lower in ampullary carcinomas than in pancreatic carcinomas. When these discriminatory microRNAs were applied to liver metastases, they were correctly predicted for the tissue of origin. Although this study is limited by small sample size, striking difference in microRNA expression and concordant expression of discriminating microRNAs in primary tumors and metastases suggest that these novel discriminatory microRNAs warrant future validation.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-215"}
{"PMID":27464352,"Year":2016,"Title":"The potential diagnostic value of serum microRNA signature in patients with pancreatic cancer.","Abstract":"Biomarkers for early diagnosis of patients with pancreatic cancer (PC) are needed. Our aim was to identify panels of miRNAs in serum in combination with CA 19-9 for use in the diagnosis of PC. Four hundred seventeen patients with PC were included prospectively from Denmark (n = 306) and Germany (n = 111). Controls included 59 patients with chronic pancreatitis (CP) and 248 healthy subjects (HS). MiRNAs were analyzed in pretreatment serum samples from 3 cohorts: discovery cohort (754 human miRNAs, TaqMan((R)) Human MicroRNA assay, Applied Biosystem; PC n = 133, controls n = 72); training cohort (34 miRNAs, real-time qPCR using the Fluidigm BioMark System; PC n = 198, controls n = 184); validation cohort (13 miRNAs, real-time qPCR using the Fluidigm BioMark System; PC n = 86, controls n = 51). We found that 34 miRNAs in serum from PC patients in the discovery cohort were expressed differently than in controls. These miRNAs were tested in the training cohort, and four diagnostic panels were constructed that included 5 or 12 miRNAs (miR-16, -18a, -20a, -24, -25, -27a, -29c, -30a.5p, -191, -323.3p, -345 and -483.5p). Diagnostic accuracy of detecting PC in the training cohort was AUC (Index I 0.85; II 0.87; III 0.85; IV 0.95; CA 19-9 0.93); specificity (I 0.71; II 0.76; III 0.66; IV 0.90 (fixed sensitivity at 0.85); CA 19-9 0.93). Combining serum CA 19-9 and Index II best discriminated Stages I and II PC from HS [AUC 0.93 (0.90-0.96), sensitivity 0.77 (0.69-0.84), specificity 0.94 (0.90-0.96) and accuracy 0.88 (0.84-0.91)]. In conclusion, we identified four diagnostic panels based on 5 or 12 miRNAs in serum that could distinguish patients with PC from HS and CP.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-29"}
{"PMID":19747919,"Year":2009,"Title":"Retinoic acid receptor antagonists inhibit miR-10a expression and block metastatic behavior of pancreatic cancer.","Abstract":"BACKGROUND & AIMS: The infiltrating ductal adenocarcinoma of the pancreas is among the most lethal of all solid malignancies, largely owing to a high frequency of early metastasis. We identified microRNA-10a (miR-10a) as an important mediator of metastasis formation in pancreatic tumor cells and investigated the upstream and downstream regulatory mechanisms of miR-10a. METHODS: Northern blot analysis revealed increased expression levels of miR-10a in metastatic pancreatic adenocarcinoma. The role of miR-10a was analyzed by Morpholino and short interfering RNA transfection of pancreatic carcinoma cell lines and resected specimens of human pancreatic carcinoma. Metastatic behavior of primary pancreatic tumors and cancer cell lines was tested in xenotransplantation experiments in zebrafish embryos. RESULTS: We show that miR-10a expression promotes metastatic behavior of pancreatic tumor cells and that repression of miR-10a is sufficient to inhibit invasion and metastasis formation. We further show that miR-10a is a retinoid acid target and that retinoic acid receptor antagonists effectively repress miR-10a expression and completely block metastasis. This antimetastatic activity can be prevented by specific knockdown of HOX genes, HOXB1 and HOXB3. Interestingly, suppression of HOXB1 and HOXB3 in pancreatic cancer cells is sufficient to promote metastasis formation. CONCLUSIONS: These findings suggest that miR-10a is a key mediator of metastatic behavior in pancreatic cancer, which regulates metastasis via suppression of HOXB1 and HOXB3. Inhibition of miR-10a expression (with retinoic acid receptor antagonists) or function (with specific inhibitors) is a promising starting point for antimetastatic therapies.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-10"}
{"PMID":23139258,"Year":2013,"Title":"The good, the bad and the ugly: a tale of miR-101, miR-21 and miR-155 in pancreatic intraductal papillary mucinous neoplasms.","Abstract":"BACKGROUND: This multicenter study evaluated three candidate microRNAs (miRNAs) (miR-21, miR-155 and miR-101) as potential biomarkers in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. PATIENTS AND METHODS: miRNA expression was quantified by quantitative RT-PCR in 86 laser-microdissected specimens, including 65 invasive IPMNs, 16 non-invasive IPMNs and 5 normal pancreatic ductal tissues. Univariate and multivariate analyses compared miRNAs and clinical parameters with overall (OS) and disease-free survival (DFS). RESULTS: miR-21 and miR-155 were up-regulated in invasive IPMNs compared with non-invasive IPMNs, as well as in non-invasive IPMNs compared with normal tissues. Conversely, miR-101 levels were significantly higher in non-invasive IPMNs and normal tissues compared with invasive IPMNs. High levels of miR-21 were associated with worse OS [hazard ratio (HR) = 2.47, 95% confidence interval (CI) = 1.37-5.65, P = 0.0047]. Patients with high-miR-21 expression also had a shorter median DFS (10.9 versus 29.9 months, P = 0.01). Multivariate analysis confirmed miR-21 as independently prognostic for mortality and disease progression (death risk: HR = 3.3, 95% CI = 1.5-7.0, P = 0.02; progression risk: HR = 2.3, 95% CI = 1.2-4.8, P = 0.02), as well as positive lymph-node status (death risk: HR = 2.6, 95% CI = 1.1-6.3, P = 0.03; progression risk: HR = 2.2, 95% CI = 1.0-4.8, P = 0.04). CONCLUSIONS: miR-21, miR-155 and miR-101 showed significant differences in invasive versus non-invasive IPMNs. miR-21 emerged as an independent prognostic biomarker in invasive IPMNs and should be validated in prospective studies.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-155"}
{"PMID":26195069,"Year":2015,"Title":"Pancreatic cancer-secreted miR-155 implicates in the conversion from normal fibroblasts to cancer-associated fibroblasts.","Abstract":"Cancer-associated fibroblasts (CAF) are a major constituent of the pancreatic cancer microenvironment and that the meaning is as intended. Pancreatic cancer cells can induce normal fibroblasts to convert into CAF and, reciprocally, CAF promote tumor invasions and proliferations. The mechanism of the conversion from normal fibroblasts (NF) to CAF remains unclear. MicroRNA are short non-coding RNA involved in the post-transcription gene regulation, which have been defined as an imperative controller in tumor invasions, proliferations and colony formations. Microvesicles (MV) have been proved to be an important mediator of intercellular communication and can selectively transport secreted microRNA from a donor cell into a recipient cell. In this study, we isolated primary pancreatic fibroblasts from wild type C57 mice and co-cultured them with pancreatic cancer cell lines, BxPC-3 and SW1990, and observed the conversion from NF to CAF, or at least CAF-like cells. This phenomenon could also be replicated in primary fibroblasts treated with MV separated from a cancer cell media. We identified that miR-155 was upregulated in PaC-derived MV and we confirmed that normal fibroblasts could convert into CAF after MV containing miR-155 had been taken up. TP53INP1 is a target of miR-155 in fibroblasts and a downregulation of TP53INP1 protein levels could contribute to the fibroblasts' activation. These results indicated that pancreatic cancer cells might reprogram normal adjacent fibroblasts into CAF by means of secreted MV containing miR-155. Targeting the circulating microRNA might be a potential therapy for malignant tumors.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-155"}
{"PMID":22466166,"Year":2012,"Title":"MicroRNA expression aids the preoperative diagnosis of pancreatic ductal adenocarcinoma.","Abstract":"OBJECTIVES: This study aimed to evaluate microRNA (miRNA) expression in pancreatic resection specimens and fine needle aspiration biopsies and determine which, if any, miRNAs aid the distinction between benign and malignant pancreatic tumors in limited cytology material. METHODS: Resection specimens containing adenocarcinoma (n = 17), intraductal papillary mucinous neoplasms (n = 11), and nonneoplastic tissues (n = 15) were evaluated for miR-21, miR-221, miR-100, miR-155, and miR-181b expression by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and a subset of carcinomas and intraductal papillary mucinous neoplasms was analyzed with miRNA microarrays. Cellblocks containing carcinoma (n = 26) or benign pancreatic lesions (n = 11) from fine needle aspiration biopsies were subjected to qRT-PCR for miR-21, miR-221, miR-181b, miR-196a, and miR-217. RESULTS: Carcinomas showed higher expression of miR-21, miR-221, miR-155, miR-100, and miR-181b than benign lesions by qRT-PCR, and overexpression of miR-21, miR-221, and miR-181b was confirmed by microarray analysis. Cellblocks containing carcinoma showed higher expression of miR-21, miR-221, and miR-196a than those from benign lesions (P < 0.001, P = 0.009, and P < 0.001, respectively). CONCLUSIONS: Pancreatic ductal adenocarcinomas show differential expression of miRNAs compared to benign pancreatic lesions. A select panel of miRNAs aids the distinction between pancreatic lesions in cytology specimens.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-196"}
{"PMID":26683934,"Year":2015,"Title":"High Expression of MicroRNA-196a Indicates Poor Prognosis in Resected Pancreatic Neuroendocrine Tumor.","Abstract":"There is limited data on miRNA expression in pancreatic neuroendocrine tumors (PanNETs). In this study, we aimed to identify miRNAs that could be potential prognostic biomarkers of PanNETs in patients who underwent curative surgery. For miRNA target screening, 2 primary PanNETs and corresponding liver metastases were screened for miRNA expression by the NanoString nCounter analysis. Candidate miRNAs were selected by >/=2-fold difference of expression between metastatic versus primary tumor. For miRNA target validation, quantitative real-time PCR was performed for candidate miRNAs on 37 PanNETs and matched nonneoplastic pancreata, and the miRNA levels were correlated with the clinicopathological features and patient survival data. Eight miRNAs (miRNA-27b, -122, -142-5p, -196a, -223, -590-5p, -630, and -944) were selected as candidate miRNAs. Only miR-196a level was significantly associated with stage, and mitotic count. When PanNETs were stratified into high (n = 10) and low (n = 27) miRNA-196a expression groups, miRNA-196a-high PanNETs were significantly associated with advanced pathologic T stage (50.0% vs 7.4%), N stage (50.0% vs 3.7%), higher mitotic counts (60.0% vs 3.7%), and higher Ki-67-labeling indices (60.0% vs 22.2%). In addition, high miRNA-196a expression was significantly associated with decreased overall survival (P = 0.046) and disease-free survival (P < 0.001) during a median follow-up of 37.9 months with the hazard ratio for recurrence of 16.267 (95% confidence interval = 1.732-153.789; P = 0.015). MiRNA-196a level may be a promising prognostic marker of recurrence in resected PanNETs, although further experimental investigation would be required.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-122"}
{"PMID":30767148,"Year":2019,"Title":"MiRNA-3653 Is a Potential Tissue Biomarker for Increased Metastatic Risk in Pancreatic Neuroendocrine Tumours.","Abstract":"Pancreatic neuroendocrine tumours (PNETs) are relatively uncommon, accounting for 1-2% of all pancreatic neoplasms. Tumour grade (based on the Ki67 proliferative index and mitotic rate) is associated with metastatic risk across large cohorts; however, predicting the behaviour of individual tumours can be difficult. Therefore, any tool which could further stratify metastatic risk may be clinically beneficial. We sought to investigate microRNA (miRNA) expression as a marker of metastatic disease in PNETs. Tumours from 37 patients, comprising 23 with locoregional disease (L) and 14 with distant metastases (DM), underwent miRNA profiling. In total 506 miRNAs were differentially expressed between the L and DM groups, with four miRNAs (miR-3653 upregulated, and miR-4417, miR-574-3p and miR-664b-3p downregulated) showing statistical significance. A database search demonstrated that miRNA-3653 was associated with ATRX abnormalities. Mean survival between the two groups was correlated with mean expression of miRNA-3653; however, this did not reach statistical significance (p = 0.204). Although this is a small study, we conclude that miRNA-3653 upregulation may be associated with an increased risk of metastatic disease in PNETS, perhaps through interaction with ATRX and the alternate lengthening of telomeres pathway.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-3653"}
{"PMID":28460450,"Year":2017,"Title":"Epigenetically altered miR-1247 functions as a tumor suppressor in pancreatic cancer.","Abstract":"Altered expression of microRNAs has been strongly implicated in human cancers, and growing evidence is emerging that a number of miRNAs are downregulated in cancer associated with CpG island hypermethylation. Although pancreatic cancer is one of the most malignant human cancers, the roles of miRNAs underlying the tumorigenesis of pancreatic cancer are still poorly understood. In the present study, we explored the molecular functional role of microRNA-1247 as tumor suppressor associated with epigenetic alteration in pancreatic cancer. CpG islands methylation of miR-1247 is frequently observed in various pancreatic cancer cell lines and in primary pancreatic tumors, but not in normal pancreatic tissue. Ectopic expression of miR-1247 in five pancreatic cancer cell lines results in suppressing of cell growth, proliferation, migration, and invasion in vitro and tumorigenicity of pancreatic cancer cells in vivo. Interestingly, we found one putative target gene of miR-1247, regulator of chromosome condensation 2 (RCC2), harbored miR-1247 target sequences in the 3' UTR of its mRNA. In functional studies in vitro to understand the interaction between miR-1247 and RCC2, decreasing of RCC2 gene expression by miR-1247 was observed by immunoblotting and immunohistochemistry at both mRNA and protein levels. Moreover, luciferase reporter assay confirmed that RCC2 was a direct target of miR-1247. Taken together, our data suggest that CpG island hypermethylation of miR-1247 is responsible for its downregulation in pancreatic cancer, and ectopic expression of miR-1247 functions as a potential tumor suppressor targeting RCC2 in pancreatic cancer cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1247"}
{"PMID":28466015,"Year":2017,"Title":"Evaluation of Plasma MicroRNAs as Diagnostic and Prognostic Biomarkers in Pancreatic Adenocarcinoma: miR-196a and miR-210 Could Be Negative and Positive Prognostic Markers, Respectively.","Abstract":"Background. Identifying diagnostic and prognostic biomarkers that could be targeted in the therapy of pancreatic cancer is essential. Objective. Investigations were conducted with respect to plasma miRNA (miR-21, miR-210, miR-155, miR-196a, miR-20a, and miR-25) expression and clinicopathologic factors to evaluate the prognostic value of miRNAs in pancreatic ductal adenocarcinoma (PDAC). Methods. Plasma miRNAs were detected by real-time quantitative PCR, and the association with clinicopathologic factors was subsequently performed by univariate and multivariate analyses. Results. Six miRNAs expressed significantly higher in PDAC patients than in normal individuals were identified. Receiver operating characteristic (ROC) curves were constructed. It was evident that miRNA expression associated with PDAC, lymph node metastasis, serosal infiltration, and comprehensive therapy reached significance for overall survival. High miR-196a expression was associated with poor survival (P = 0.001), whereas high miR-210 expression was significantly associated with improved survival (P = 0.003). Multivariate survival analysis indicated that the miR-210 and miR-196a expression signature, lymph node metastasis, and comprehensive therapy were independent factors affecting overall survival. Conclusions. MiRNA expression profile is distinctive in PDAC. Aberrant expression of certain miRNAs was remarkably involved in shaping the overall survival time, which include miR-196a overexpression and decreased miR-210 expression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-25"}
{"PMID":25087086,"Year":2014,"Title":"Bioinformatics method to predict two regulation mechanism: TF-miRNA-mRNA and lncRNA-miRNA-mRNA in pancreatic cancer.","Abstract":"Altered expressions of microRNAs (miRNAs) are reported in pancreatic cancer and associate with cancer pathogenesis, apoptosis, and cell growth, thereby functioning as either tumor suppressors or oncogenes. However, the majority of studies focus on defining the regulatory functions of miRNAs, whereas few investigations are directed toward assessing how the miRNA themselves are transcriptionally regulated. In this study, integration of published multi-level expression data and bioinformatics computational approach was used to predict two regulation mechanisms: transcription factors (TF)-miRNA-mRNA regulation and long non-coding RNA(lncRNA)-miRNA-mRNA regulation. To identify differentially expressed mRNAs, miRNAs, and lncRNAs, we integrated microarray expression data in pancreatic cancer tissues and normal tissues. Combination of differentially expressed mRNAs and miRNAs with miRNA-mRNA interactions based on crosslinking and immunoprecipitation followed by high-throughput sequencing (CLIP-Seq) data from StarBas, we constructed miRNA-mRNA regulatory network. Then we constructed two regulatory networks including TF-miRNA-mRNA and lncRNA-miRNA-mRNA based on chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from ChIPBase and CLIP-Seq data. A total of 4385 mRNAs, 500 miRNAs, and 21 lncRNAs were differentially expressed, of which, 18 mRNAs and 54 miRNAs are with high confidence. In miRNA-mRNA regulatory network, interrelated miRNAs target 1701 differentially regulated mRNAs. By constructing regulatory network, 19miRNAs including hsa-miR-137, hsa-miR-206, hsa-miR-429, hsa-miR-320d, and hsa-miR-320c are predicted to participate in lncRNA-miRNA-mRNA regulation. Furthermore, 8 miRNAs including hsa-mir-137, hsa-mir-206, hsa-mir-429, hsa-mir-375, hsa-mir-326, hsa-mir-217, hsa-mir-301b, and hsa-mir-184 are predicted to participate in TF-miRNA-mRNA regulation. In an integrated data analysis, we reveal large-scale effects of interrelated miRNAs and provide a model for predicting the mechanism of miRNAs disorder. Our study provides a new insight into understanding the transcriptional regulation of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-137"}
{"PMID":21159816,"Year":2010,"Title":"Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway.","Abstract":"Although activating mutations in RAS oncogenes are known to result in aberrant signaling through multiple pathways, the role of microRNAs (miRNAs) in the Ras oncogenic program remains poorly characterized. Here we demonstrate that Ras activation leads to repression of the miR-143/145 cluster in cells of human, murine, and zebrafish origin. Loss of miR-143/145 expression is observed frequently in KRAS mutant pancreatic cancers, and restoration of these miRNAs abrogates tumorigenesis. miR-143/145 down-regulation requires the Ras-responsive element-binding protein (RREB1), which represses the miR-143/145 promoter. Additionally, KRAS and RREB1 are targets of miR-143/miR-145, revealing a feed-forward mechanism that potentiates Ras signaling.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-143"}
{"PMID":22117151,"Year":2011,"Title":"microRNAs as markers of survival and chemoresistance in pancreatic ductal adenocarcinoma.","Abstract":"microRNAs (miRs) are a recently recognized class of noncoding short RNAs, 17-25 nucleotides in length, that play a role in post-transcriptional gene regulation by translational repression and/or mRNA degradation. Various miRs have been highlighted in pancreatic cancer development and metastasis, and as potential clinical diagnostic/prognostic biomarkers. Recently, studies have indicated that miRs are responsible for resistance to chemotherapeutic agents. The miR-10b has been identified as a 'metastamiR' in various tumor types, notably breast cancer, but data surrounding its relevance in pancreatic ductal adenocarcinoma has been sparse. The evaluated article presents data indicating that miR-10b is upregulated in pancreatic ductal adenocarcinoma and can be used as a diagnostic marker in endoscopic ultrasound-guided fine-needle aspiration biopsies of suspicious pancreatic lesions. In addition, miR-10b may be able to guide neoadjuvant gemcitabine-based chemoradiotherapy and predict metastatic-free survival and overall survival.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-10"}
{"PMID":24060073,"Year":2013,"Title":"[Target prediction and verification of miR-27a in pancreatic cancer].","Abstract":"OBJECTIVE: To predict and verify the target gene of miR-27a in pancreatic cancer by combining the result of comparative proteome analysis. METHODS: The bioinformatics softwares of TargetScan,PicTar and miRanda were used to predict the possible target genes of miR-27a. Based on the results of comparative proteomics analysis, possible candidates of the target genes were selected. Expression vector of target gene 3'UTR was constructed, and then target gene was verified by dual-luciferase reporter assay system. The PANC-1 and BxPC-3 pancreatic cancer cells were treated with miR-27a mimics or negative control for 48 h. Western blot analysis was used to verify alterations of protein expression of the genes. RESULTS: PSMA1 was selected as the candidate target gene of miR-27a by bioinformatics prediction and comparative proteome analysis. Dual-luciferase reporter assay showed that miR-27a decreased luciferase activity in cells co-transfected with pmirGLO-PSMA1-WT, compared to the negative control, although significant difference of luciferase activity was not observed in cells co-transfected with pmirGLO-PSMA1-MUT between the two groups. The protein level of PSMA1 was down-regulated in pancreatic cancer cells transfected with miR-27a mimics in comparison with pancreatic cancer cells transfected with negative control. CONCLUSION: PSMA1 is the direct target gene of miR-27a in pancreatic cancer.","Language":"chi","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-27"}
{"PMID":19551852,"Year":2010,"Title":"Elevated expression of microRNAs 155, 203, 210 and 222 in pancreatic tumors is associated with poorer survival.","Abstract":"Pancreatic cancer is the eighth most common cancer and has an overall 5-year survival rate lower than 10%. Because of their ability to regulate gene expression, microRNAs can act as oncogenes or tumor-suppressor genes and so have garnered interest as possible prognostic and therapeutic markers during the last decade. However, the prognostic value of microRNA expression in pancreatic cancer has not been thoroughly investigated. We measured the levels of miR-155, miR-203, miR-210, miR-216, miR-217 and miR-222 by quantitative RT-PCR in a cohort of 56 microdissected pancreatic ductal adenocarcinomas (PDAC). These microRNAs were chosen as they had previously been shown to be differentially expressed in pancreatic tumors compared to normal tissues. The possible association of microRNA expression and patients' survival was examined using multivariate Cox's regression hazard analyses. Interestingly, significant correlations between elevated microRNA expression and overall survival were observed for miR-155 (RR = 2.50; p = 0.005), miR-203 (RR = 2.21; p = 0.017), miR-210 (RR = 2.48; p = 0.005) and miR-222 (RR = 2.05; p = 0.035). Furthermore, tumors from patients demonstrating elevated expression levels of all 4 microRNAs possessed a 6.2-fold increased risk of tumor-related death compared to patients whose tumors showed a lower expression of these microRNAs. This study provides the first evidence for an oncogenic activity of miR-155, miR-203, miR-210 and miR-222 in the development of pancreatic cancer as has been reported for other tumor types. Furthermore, the putative target genes for these microRNAs suggest a complex signaling network that can affect PDAC tumorigenesis and tumor progression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-222"}
{"PMID":31187215,"Year":2019,"Title":"miR-17-92 and miR-106b-25 clusters regulate beta cell mitotic checkpoint and insulin secretion in mice.","Abstract":"AIMS/HYPOTHESIS: Adult beta cells in the pancreas are the sole source of insulin in the body. Beta cell loss or increased demand for insulin impose metabolic challenges because adult beta cells are generally quiescent and infrequently re-enter the cell division cycle. The aim of this study is to test the hypothesis that a family of proto-oncogene microRNAs that includes miR-17-92 and miR-106b-25 clusters regulates beta cell proliferation or function in the adult endocrine pancreas. METHODS: To elucidate the role of miR-17-92 and miR-106b-25 clusters in beta cells, we used a conditional miR-17-92/miR-106b-25 knockout mouse model. We employed metabolic assays in vivo and ex vivo, together with advanced microscopy of pancreatic sections, bioinformatics, mass spectrometry and next generation sequencing, to examine potential targets of miR-17-92/miR-106b-25, by which they might regulate beta cell proliferation and function. RESULTS: We demonstrate that miR-17-92/miR-106b-25 regulate the adult beta cell mitotic checkpoint and that miR-17-92/miR-106b-25 deficiency results in reduction in beta cell mass in vivo. Furthermore, we reveal a critical role for miR-17-92/miR-106b-25 in glucose homeostasis and in controlling insulin secretion. We identify protein kinase A as a new relevant molecular pathway downstream of miR-17-92/miR-106b-25 in control of adult beta cell division and glucose homeostasis. CONCLUSIONS/INTERPRETATION: The study contributes to the understanding of proto-oncogene miRNAs in the normal, untransformed endocrine pancreas and illustrates new genetic means for regulation of beta cell mitosis and function by non-coding RNAs. DATA AVAILABILITY: Sequencing data that support the findings of this study have been deposited in GEO with the accession code GSE126516.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-106"}
{"PMID":26807325,"Year":2015,"Title":"Noninvasive urinary miRNA biomarkers for early detection of pancreatic adenocarcinoma.","Abstract":"Currently, the majority of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) present with locally invasive and/or metastatic disease, resulting in five-year survival of less than 5%. The development of an early diagnostic test is, therefore, expected to significantly impact the patient's prognosis. In this study, we successfully evaluated the feasibility of identifying diagnostic cell free microRNAs (miRNAs) for early stage PDAC, through the analysis of urine samples. Using Affymetrix microarrays, we established a global miRNA profile of 13 PDAC, six chronic pancreatitis (CP), and seven healthy (H) urine specimens. Selected differentially expressed miRNAs were subsequently investigated using an independent technique (RT-PCR) on 101 urine samples including 46 PDAC, 29 CP and 26 H. Receiver operating characteristic (ROC) and logistic regression analyses were applied to determine the discriminatory potential of the candidate miRNA biomarkers. Three miRNAs (miR-143, miR-223, and miR-30e) were significantly over-expressed in patients with Stage I cancer when compared with age-matched healthy individuals (P=0.022, 0.035 and 0.04, respectively); miR-143, miR-223 and miR-204 were also shown to be expressed at higher levels in Stage I compared to Stages II-IV PDAC (P=0.025, 0.013 and 0.008, respectively). Furthermore, miR-223 and miR-204 were able to distinguish patients with early stage cancer from patients with CP (P=0.037 and 0.036). Among the three biomarkers, miR-143 was best able to differentiate Stage I (n=6) from healthy (n=26) with area under the curve (AUC) of 0.862 (95% CI 0.695-1.000), with sensitivity (SN) of 83.3% (95% CI 50.0-100.0), and specificity (SP) of 88.5% (95% CI 73.1-100.0). The combination of miR-143 with miR-30e was significantly better at discriminating between these two groups, achieving an AUC of 0.923 (95% CI 0.793-1.000), with SN of 83.3% (95% CI 50.0-100.0) and SP of 96.2% (95% CI 88.5-100.0). In this feasibility study, we demonstrate for the first time the utility of miRNA biomarkers for non-invasive, early detection of PDAC in urine specimens.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-143"}
{"PMID":30344707,"Year":2018,"Title":"MicroRNA-217 functions as a tumor suppressor in cervical cancer cells through targeting Rho-associated protein kinase 1.","Abstract":"The abnormal expression of microRNAs (miRNAs/miRs) has been widely reported in various tumor types. miR-217 was demonstrated to be aberrantly expressed in a number of tumors, including pancreatic adenocarcinoma and osteosarcoma; however, its specific expression pattern has never been investigated in cervical cancer cells. Compared with normal control, the level of Rho-associated protein kinase 1 (ROCK1) expression was markedly increased in cervical cancer tissues and cells compared with that in non-cancerous tissues and cells. The expression of miR-217 was significantly reduced in cervical cancer tissues and cell lines. Overexpression of miR-217 could suppress colony formation and the cell invasion capacity of SiHa and HeLa cells. Flow cytometry indicated that miR-217 significantly increased cell apoptosis in SiHa and HeLa cells. Dual-luciferase reporter assays demonstrated that ROCK1 was a target gene of miR-217. In addition, overexpression of ROCK1 also led to an increased invasion capacity in SiHa cells, even when miR-217 was inhibited, indicating that the anti-invasive effects of miR-217 were mediated through ROCK1. In summary, the results of the present study indicated that miR-217 functions as a tumor suppressor in cervical cancer cells, primarily by targeting ROCK1.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-217"}
{"PMID":28239461,"Year":2017,"Title":"Tissue MicroRNA profiles as diagnostic and prognostic biomarkers in patients with resectable pancreatic ductal adenocarcinoma and periampullary cancers.","Abstract":"BACKGROUND: The aim of this study was to validate previously described diagnostic and prognostic microRNA expression profiles in tissue samples from patients with pancreatic cancer and other periampullary cancers. METHODS: Expression of 46 selected microRNAs was studied in formalin-fixed paraffin-embedded tissue from patients with resected pancreatic ductal adenocarcinoma (n = 165), ampullary cancer (n=59), duodenal cancer (n = 6), distal common bile duct cancer (n = 21), and gastric cancer (n = 20); chronic pancreatitis (n = 39); and normal pancreas (n = 35). The microRNAs were analyzed by PCR using the Fluidigm platform. RESULTS: Twenty-two microRNAs were significantly differently expressed in patients with pancreatic cancer when compared to healthy controls and chronic pancreatitis patients; 17 miRNAs were upregulated (miR-21-5p, -23a-3p, -31-5p, -34c-5p, -93-3p, -135b-3p, -155-5p, -186-5p, -196b-5p, -203, -205-5p, -210, -222-3p, -451, -492, -614, and miR-622) and 5 were downregulated (miR-122-5p, -130b-3p, -216b, -217, and miR-375). MicroRNAs were grouped into diagnostic indices of varying complexity. Ten microRNAs associated with prognosis were identified (let-7 g, miR-29a-5p, -34a-5p, -125a-3p, -146a-5p, -187, -205-5p, -212-3p, -222-5p, and miR-450b-5p). Prognostic indices based on differences in expression of 2 different microRNAs were constructed for pancreatic and ampullary cancer combined and separately (30, 5, and 21 indices). CONCLUSION: The study confirms that pancreatic cancer tissue has a microRNA expression profile that is different from that of other periampullary cancers, chronic pancreatitis, and normal pancreas. We identified prognostic microRNAs and microRNA indices that were associated with shorter overall survival in patients with radically resected pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-125"}
{"PMID":30006373,"Year":2018,"Title":"Prognostic relevance of proliferation-related miRNAs in pancreatic neuroendocrine neoplasms.","Abstract":"Objective Pancreatic neuroendocrine neoplasms (PanNENs) are rare tumors arising from the endocrine pancreas, however their prognosis differs significantly upon their proliferative state which is characterized by histopathological grading. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to identify miRNAs with altered expression upon proliferation which can be used as prognostic biomarkers in PanNENs. Methods MiRNA expression profiles of 40 PanNENs were downloaded from Gene Expression Omnibus and were reanalyzed upon tumor grades (discovery cohort). Results of the reanalysis were confirmed by qRT-PCR analysis of 5 miRNAs on an independent validation cohort of sixty three primary PanNEN samples. Cox proportional hazards survival regression model was fit for both univariate and multivariate analysis to determine the miRNAs' effect on progression-free and overall survival. Results 19 miRNAs displayed differential expression between tumor grades. The altered expression of 3 out of 5 chosen miRNAs was successfully validated; hsa-miR-21, hsa-miR-10a and hsa-miR-106b were up-regulated in more proliferative PanNENs compared to grade 1 tumors. In univariate analysis, higher expression of tissue hsa-miR-21, hsa-miR-10a and hsa-miR-106b expression of primary PanNENs predicted worse progression-free and overall survival, however multivariate analysis only confirmed the expression of hsa-miR-21 as an independent prognostic factor. Conclusions The expression of hsa-miR-106b, hsa-miR-10a and especially hsa-miR-21 has prognostic relevance regarding progression-free and overall survival in patients with PanNENs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-10"}
{"PMID":31510100,"Year":2019,"Title":"Differentially Expressed microRNAs in MIA PaCa-2 and PANC-1 Pancreas Ductal Adenocarcinoma Cell Lines are Involved in Cancer Stem Cell Regulation.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and thus better understanding of its molecular pathology is crucial for us to devise more effective treatment of this deadly disease. As cancer cell line remains a convenient starting point for discovery and proof-of-concept studies, here we report the miRNA expression characteristics of two cell lines, MIA PaCa-2 and PANC-1, and discovered three miRNAs (miR-7-5p, let-7d, and miR-135b-5p) that are involved in cancer stem cells (CSCs) suppression. After transfection of each miRNA's mimic into PANC-1 cells which exhibits higher stemness feature than MIA-PaCa-2 cells, partial reduction of CSC surface markers and inhibition of tumor sphere formation were observed. These results enlighten us to consider miRNAs as potential therapeutic agents for pancreatic cancer patients via specific and effective inhibition of CSCs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"let-7"}
{"PMID":27080237,"Year":2016,"Title":"Stratification of Digestive Cancers with Different Pathological Features and Survival Outcomes by MicroRNA Expression.","Abstract":"MicroRNAs (miRNAs) are aberrantly expressed in virtually all cancer types, including digestive cancers. Herein, we aggregated and systematically analyzed miRNA expression profiles of 1765 tumor samples, including esophageal, gastric, liver, pancreatic, colon and rectal cancers, obtained through small RNA sequencing by The Cancer Genome Atlas. We found that digestive cancers of different tissue origins could be differentiated according to their miRNA expression profiles. In particular, esophageal squamous cell carcinoma and esophageal adenocarcinoma exhibited distinct miRNA expression patterns. Thirteen (e.g. miR-135b, miR-182) and sixteen (e.g. miR-139, miR-133a-1, miR-490) miRNAs were commonly upregulated and downregulated in more than four cancer types, respectively. Pertinent to pathological features, low miR-181d expression was associated with microsatellite instability in colon and gastric cancers whereas low miR-106a expression was associated with hepatitis B virus infection in hepatocellular carcinoma. Progression in colon cancer could also be predicted by low let-7f-2 and high miR-106a expression. Molecular subtypes with distinct prognostic outcomes independent of tumor-node-metastasis staging were identified in hepatocellular carcinoma and colon cancer. In total, 4 novel and 6 reported associations between specific miRNAs and patients' survival were identified. Collectively, novel miRNA markers were identified to stratify digestive cancers with different pathological features and survival outcomes.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-139"}
{"PMID":22929886,"Year":2012,"Title":"MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer.","Abstract":"BACKGROUND: A major challenge to the development of biomarkers for pancreatic cancer (PC) is the small amount of tissue obtained at the time of diagnosis. Single-gene analyses may not reliably predict biology of PC because of its complex molecular makeup. MicroRNA (miRNA) profiling may provide a more informative molecular interrogation of tumours. The primary objective of this study was to determine the feasibility of performing miRNA arrays and quantitative real-time PCR (qRT-PCR) from archival formalin-fixed paraffin-embedded (FFPE) cell blocks obtained from fine-needle aspirates (FNAs) that is the commonest diagnostic procedure for suspected PC. METHODS: MicroRNA expression profiling was performed on FFPE from FNA of suspicious pancreatic masses. Subjects included those who had a pathological diagnosis of pancreatic adenocarcinoma and others with a non-malignant pancreatic histology. Exiqon assay was used to quantify miRNA levels and qRT-PCR was used to validate abnormal expression of selected miRNAs. RESULTS: A total of 29 and 15 subjects had pancreatic adenocarcinoma and no evidence of cancer, respectively. The RNA yields per patient varied from 25 to 100 ng. Profiling demonstrated deregulation of over 228 miRNAs in pancreatic adenocarcinoma of which the top 7 were further validated by qRT-PCR. The expression of let-7c, let-7f, and miR-200c were significantly reduced in most patients whereas the expression of miR-486-5p and miR-451 were significantly elevated in all pancreas cancer patients. MicroRNAs let-7d and miR-423-5p was either downregulated or upregulated with a significant inter-individual variation in their expression. CONCLUSION: This study demonstrated the feasibility of using archival FFPE cell blocks from FNAs to establish RNA-based molecular signatures unique to pancreatic adenocarcinoma with potential applications in clinical trials for risk stratification, patient selection, and target validation.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"let-7"}
{"PMID":24520289,"Year":2014,"Title":"miR-203 inhibits tumor cell migration and invasion via caveolin-1 in pancreatic cancer cells.","Abstract":"Pancreatic cancer is one of the most lethal malignant diseases with the poorest prognosis and is the fourth leading cause of tumor-associated mortality in the industrialized world. microRNAs (miRNAs or miRs) are small noncoding RNAs of approximately 22 nucleotides long that are able to function as oncogenes or tumor suppressors in human cancer. In our study, overexpression of miR-203 in Panc-1 cells is sufficient to reduce migratory ability and invasiveness, and to induce upregulation of epithelial markers (Snail, ZO-1 and beta-catenin) followed by a decrease of mesenchymal marker expression (Zeb-1, vimentin and fibronectin). We also found that the caveolin-1 mRNA or protein levels are modulated by miR-203 in Panc-1 cells. We found that exogenous miR-203 altered the level of cell migration and invasion, and the expression of associated proteins following caveolin-1 knockdown by small interfering RNA. These results demonstrate that miR-203 inhibits cell migration and invasion via caveolin-1 in pancreatic cancer cells, suggest that miR-203 expression may be a useful indicator of the metastatic potential and provide a new therapeutic target in this common malignancy.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-203"}
{"PMID":21099286,"Year":2009,"Title":"MiR-30 family and EMT in human fetal pancreatic islets.","Abstract":"Small, non-coding ribonucleotides called micro RNAs (miRNAs) have recently emerged as important regulators of cell function. MiRNAs regulate gene expression mainly by binding to the 3' UTR of mRNAs and thereby inhibit the translation of target mRNAs. The abundance of many miRNAs is altered under physiological and pathophysiological conditions, such as cancer and neurodegeneration. Recent data suggest that miRNAs also have an important role in regulation of insulin gene transcription, insulin secretion, and pancreatic islet cell function. An interesting study by Joglekar et al. published in this issue of ISLETS suggests that the miR-30 family of miRNAs may control the epithelial-to-mesenchymal transition of primary cultures of human pancreatic epithelial cells by negatively regulating the translation of mesenchymal gene transcripts such as vimentin. These findings are in agreement with previous data that suggest an important role for one of the miR-30 family members (miR-30d) in insulin gene expression in pancreatic beta cells. In summary, the report by Joglekar et al provides a significant advancement in understanding the role of miRNAs in pancreatic islet development and suggests that manipulation of miR-30 family of miRNA expression may provide an important means to generate and expand pancreatic beta cells from human fetal pancreatic progenitors.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-30"}
{"PMID":25549355,"Year":2014,"Title":"miR-150-5p inhibits hepatoma cell migration and invasion by targeting MMP14.","Abstract":"Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Despite progress in diagnostics and treatment of HCC, its prognosis remains poor because the molecular mechanisms underlying hepatocarcinogenesis are not well understood. In the study, we focused on identifying the role of miRNAs in HCC progression. miRNA microarray was used to analyze the differentially expressed miRNAs, and the results were validated by qPCR. We found that the miR-150-5p expression is down-regulated in HCC tissues compared with pair non-tumor tissues. miR-150-5p expression is also decreased in metastatic cancer tissues compared with pair primary tissues, indicating that miR-150-5p may be involved in HCC metastasis. Functionally, miR-150-5p inhibition significantly promotes hepatoma cell migration and invasion, whereas miR-150-5p overexpression suppresses cancer cell migration and invasion in vitro. The matrix metalloproteinase 14 (MMP14) is identified as a new target gene of miR-150-5p. miR-150-5p markedly inhibits MMP14 expression in hepatoma cells, and miR-150-5p expression is negative correlation with MMP14 expression in vivo. More important, re-expression of MMP14 in hepatoma cells partially reverses the effect of miR-150-5p in inhibiting cell invasion.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-150"}
{"PMID":31096984,"Year":2019,"Title":"Identification of potential biomarkers for diagnosis of pancreatic and biliary tract cancers by sequencing of serum microRNAs.","Abstract":"BACKGROUND: Pancreatic and biliary tract cancer (PC and BTC, respectively) are difficult to diagnose because of their clinical characteristics; however, recent studies suggest that serum microRNAs (miRNAs) might be the key to developing more efficient diagnostic methods for these cancers. METHODS: We analysed the genome-wide expression of serum miRNAs in PC and BTC patients to identify novel biomarker candidates using high-throughput sequencing and experimentally validated miRNAs on clinical samples. RESULTS: Statistical and classification analysis of the serum miRNA-expression profiles of 55 patient samples showed distinguishable patterns between cancer patients and healthy controls; however, we were unable to distinguish the two cancers. We found that three of the highest performing miRNAs were capable of distinguishing cancer patients from controls, with an accuracy of 92.7%. Additionally, dysregulation of these three cancer-specific miRNAs was demonstrated in an independent sample group by quantitative reverse transcription polymerase chain reaction. CONCLUSIONS: These results suggested three candidate serum miRNAs (mir-744-5p, mir-409-3p, and mir-128-3p) as potential biomarkers for PC and BTC diagnosis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-409"}
{"PMID":30683474,"Year":2019,"Title":"MiR-708-5p inhibits the progression of pancreatic ductal adenocarcinoma by targeting Sirt3.","Abstract":"Numbers of studies have indicated that miRNA-708 plays an important role in many types of cancer. However, the role of miRNA-708 in pancreatic ductal adenocarcinoma (PDAC) has yet to be fully elucidated. The present study aimed to investigate the role of miRNA-708-5p in the proliferation, invasion and metastasis of PDAC in vitro, as well as the underlying mechanism. We found that miRNA-708-5p was upregulated in PDAC tissues and cell lines, and high miRNA-708 expression indicated poor prognosis in PDAC patients. Besides, the CCK-8 assay, colony formation assay and transwell assay results suggested that miRNA-708-5p overexpression enhanced the ability of proliferation, invasion and migration in PDAC cell lines. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blotting and luciferase reporter assay demonstrated that SIRT3 was a direct target of miRNA-708-5p. Furthermore, a series of rescue experiments manifested that SIRT3 was involved in the oncogenic function of miRNA-708-5p in PDAC cells. Taken together, our study established a novel miRNA-708-5p/SIRT3 axis in the progression of pancreatic cancer and provided insight for pancreatic cancer treatment.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-708"}
{"PMID":27883251,"Year":2017,"Title":"MiR-892a Promotes Hepatocellular Carcinoma Cells Proliferation and Invasion Through Targeting CD226.","Abstract":"Our study is aim to investigate the influence of miR-892a on proliferative and invasive activities of human hepatocellular carcinoma (HCC) cells through regulating CD226 expression. QRT-PCR was used to detect the expression levels of miR-892a and CD226 mRNA in HCC tissues and adjacent tissues or HCC cells and normal cells whereas Western Blot was used to detect the CD226 protein expression in tissue and cell samples. Then HuH-7 cell line was selected for following assays and respectively transfected with miR-892a mimics, miR-NC, Plenti-GIII-Ubc-CD226, and Plenti-GIII-Ubc followed by qRT-PCR assay to detect the miR-892a and CD226 expression. The luciferase reporter assay was conducted to determine if miR-892a directly targeted CD226 and then CCK-8 assay, wound healing assay, Transwell assay, and flow cytometry were used to detect cell proliferation, migration, invasion ability, cell cycle, and cell apoptosis. What's more, relationships between expression levels of miR-892a or CD226 and overall survival (OS) or disease-free survival (DFS) of HCC patients were investigated based on TCGA database. MiR-892a was high-expressed in HCC tissues or cells while CD226 was low-expressed. MiR-892a directly targeted CD226 and up-regulating miR-892a expression could promote proliferative, migrating, and invasive activities of HCC cells. Different expression levels of miR-892a and CD226 both related to the prognosis of HCC. MiR-892a promotes hepatocellular carcinoma cells proliferation and invasion through regulating CD226 expression. J. Cell. Biochem. 118: 1489-1496, 2017. (c) 2016 Wiley Periodicals, Inc.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-892"}
{"PMID":28720759,"Year":2017,"Title":"Depleted tumor suppressor miR-107 in plasma relates to tumor progression and is a novel therapeutic target in pancreatic cancer.","Abstract":"This study explored decreased tumor suppressor microRNA (miRNA) plasma levels in pancreatic cancer (PCa) patients to clarify their potential as novel biomarkers and therapeutic targets. We used the microRNA array-based approach to select candidates by comparing plasma levels between PCa patients and healthy volunteers. Six down-regulated miRNAs (miR-107, miR-126, miR-451, miR-145, miR-491-5p, and miR-146b-5p) were selected. Small- and large-scale analyses using samples from 100 PCa patients and 80 healthy volunteers revealed that miR-107 was the most down-regulated miRNA in PCa patients compared with healthy volunteers (P < 0.0001; area under the receiver-operating characteristic curve, 0.851). A low miR-107 plasma level was significantly associated with advanced T stage, N stage, and liver metastasis and was an independent factor predicting poor prognosis in PCa patients (P = 0.0424; hazard ratio, 2.95). miR-107 overexpression in PCa cells induced G1/S arrest with the production of p21 and inhibited cell proliferation through the transcriptional regulation of Notch2. In vivo, the restoration and maintenance of the miR-107 plasma level significantly inhibited tumor progression in mice. Depletion of the tumor suppressor miR-107 in plasma relates to tumor progression and poor outcomes. The restoration of the plasma miR-107 level might be a novel anticancer treatment strategy for PCa.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-126"}
{"PMID":25919186,"Year":2015,"Title":"miR-144/451 Promote Cell Proliferation via Targeting PTEN/AKT Pathway in Insulinomas.","Abstract":"Insulinoma is the main type of functional pancreatic neuroendocrine tumors. The functional microRNAs (miRNAs) regulating tumor growth and progression in insulinomas are still unknown. We conducted the miRNA expression profile analysis using miRNA quantitative RT-PCR array and identified 114 differentially expressed miRNAs in human insulinomas compared with normal pancreatic islets. Forty-one differentially expressed miRNAs belonged to 7 miRNA families, and 28 miRNAs in 3 of the families localized in the epigenetically regulated imprinted chromosome 14q32 region. We validated the most significant differentially expressed miRNA cluster miR-144/451 in another 8 human normal islet samples and 25 insulinomas. Our data showed that the overexpression of miR-144/451 in mouse pancreatic beta-cells promoted cell proliferation by targeting the beta-cell regulator phosphatase and tensin homolog deleted on chromosome ten/v-akt murine thymoma viral oncogene homolog pathway and cyclin-dependent kinase inhibitor 2D. Our findings highlight the importance of functional miRNAs in insulinomas.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-144"}
{"PMID":27550813,"Year":2016,"Title":"Suppression of MicroRNA 200 Family Expression by Oncogenic KRAS Activation Promotes Cell Survival and Epithelial-Mesenchymal Transition in KRAS-Driven Cancer.","Abstract":"Oncogenic KRAS contributes to malignant transformation, antiapoptosis, and metastasis in multiple human cancers, such as lung, colon, and pancreatic cancers and melanoma. MicroRNAs (miRNAs) are endogenous 18- to 25-nucleotide noncoding small RNAs that regulate gene expression in a sequence-specific manner via the degradation of target mRNAs or inhibition of protein translation. In the present study, using array-based miRNA profiling in IMR90 and MCF10A cells expressing oncogenic KRAS, we identified that the expression of the microRNA 200 (mir-200) family was suppressed by KRAS activation and that this suppression was mediated by the transcription factors JUN and SP1 in addition to ZEB1. Restoration of mir-200 expression compromised KRAS-induced cellular transformation in vitro and tumor formation in vivo In addition, we found that enforced expression of mir-200 abrogated KRAS-induced resistance to apoptosis by directly targeting the antiapoptotic gene BCL2 Finally, mir-200 was able to antagonize the epithelial-mesenchymal transition (EMT) driven by mutant KRAS. Collectively, our results suggest that repression of endogenous mir-200 expression is one of the important cellular responses to KRAS activation during tumor initiation and progression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-200"}
{"PMID":30819221,"Year":2019,"Title":"Cross-talk among AFAP1-AS1, ACVR1 and microRNA-384 regulates the stemness of pancreatic cancer cells and tumorigenicity in nude mice.","Abstract":"BACKGROUND: Pancreatic cancer (PC) represents one of the most aggressive forms of cancer. The role of long non-coding RNAs (lncRNAs) has been highlighted in various malignancies including PC. The aim of the present study was to investigate the effects associated with actin filament-associated protein 1 antisense RNA 1 (AFAP1-AS1) on the progression of PC and the underlying mechanism. METHODS: Microarray-based gene expression profiling of PC was performed to identify PC-related lncRNAs, after which the expression of AFAP1-AS1 and cancer stem cell (CSC) markers in PC tissues and cells were determined accordingly. The potential microRNA-384 (miR-384) capable of binding to AFAP1-AS1, in addition to its ability to regulate activin receptor A type I (ACVR1) were analyzed. In order to investigate the effect of the AFAP1-AS1/miR-384/ACVR1 axis on self-renewal ability, tumorigenicity, invasion, migration and stemness of PC cells, shRNA-AFAP1-AS1, miR-384 mimic and inhibitor were cloned into cells. RESULTS: High expression of AFAP1-AS1 and ACVR1 with low expression of miR-384 were detected in PC tissues. ACVR1 was determined to be down-regulated when miR-384 was overexpressed, while the inhibition of AFAP1-AS1 decreased its ability to binding competitively to miR-384, resulting in the down-regulation of ACVR1 and enhancing miR-384 expression, ultimately inhibiting the progression of PC. The knockdown of AFAP1-AS1 or overexpression of miR-384 was confirmed to impair PC cell self-renewal ability, tumorigenicity, invasion, migration and stemness. CONCLUSIONS: Taken together, AFAP1-AS1 functions as an endogenous RNA by competitively binding to miR-384 to regulate ACVR1, thus conferring inhibitory effects on PC cell stemness and tumorigenicity.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-384"}
{"PMID":26549028,"Year":2016,"Title":"Long noncoding RNA MIR31HG exhibits oncogenic property in pancreatic ductal adenocarcinoma and is negatively regulated by miR-193b.","Abstract":"Long noncoding RNAs (lncRNAs) play important regulatory roles in a variety of diseases, including many tumors. However, the functional roles of these transcripts and mechanisms responsible for their deregulation in pancreatic ductal adenocarcinoma (PDAC) are not thoroughly understood. In this study, we discovered that lncRNA MIR31HG is markedly upregulated in PDAC. Knockdown of MIR31HG significantly suppressed PDAC cell growth, induced apoptosis and G1/S arrest, and inhibited invasion, whereas enhanced expression of MIR31HG had the opposite effects. Online database analysis tools showed that miR-193b could target MIR31HG and we found an inverse correlation between MIR31HG and miR-193b in PDAC specimens. Inhibition of miR-193b expression significantly upregulated the MIR31HG level, while overexpression of miR-193b suppressed MIR31HG's expression and function, suggesting that MIR31HG is negatively regulated by miR-193b. Moreover, using luciferase reporter and RIP assays, we provide evidence that miR-193b directly targeted MIR31HG by binding to two microRNA binding sites in the MIR31HG sequence. On the other hand, MIR31HG may act as an endogenous 'sponge' by competing for miR-193b binding to regulate the miRNA targets. Collectively, these results demonstrate that MIR31HG functions as an oncogenic lncRNA that promotes tumor progression, and miR-193b targets not only protein-coding genes but also the lncRNA, MIR31HG.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-193"}
{"PMID":28415631,"Year":2017,"Title":"LncRNA HOTAIR acts a competing endogenous RNA to control the expression of notch3 via sponging miR-613 in pancreatic cancer.","Abstract":"Pancreatic cancer is one of the most deadly cancers with a poor prognosis. Though studies have implicated the roles of microRNAs in pancreatic cancer progression, little is known about the role of miR-613 in pancreatic cancer. In the present study, the expression of miR-613 was down-regulated in pancreatic cancer tissues and cancer cell lines. Down-regulation of miR-613 was positively correlated with tumor differentiation, advanced TNM stage, nodal metastasis and shorter overall survival in patients with pancreatic cancer. Overexpression of miR-613 suppressed cell proliferation, invasion and migration, and induced cell apoptosis and cell cycle arrest at G0/G1 phase in pancreatic cancer cells. Bioinformatics analysis, luciferase reporter assay and rescue experiments showed that notch3 was a direct target of miR-613. MiR-613 was inversely correlated with notch3 expression in pancreatic cancer tissues. The long non-coding RNA, HOX transcript antisense RNA (HOTAIR) was up-regulated in both pancreatic cancer tissues and cancer cell lines, and HOTAIR suppressed the expression of miR-613 via functioning as a competing endogenous RNA. In vivo studies showed that stable overexpression of miR-613 or knock-down of HOTAIR suppressed tumor growth and also reduced the expression of notch3. In conclusion, these results suggest that HOTAIR functions as a competing endogenous RNA to regulate notch3 expression via sponging miR-613 in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-613"}
{"PMID":25087086,"Year":2014,"Title":"Bioinformatics method to predict two regulation mechanism: TF-miRNA-mRNA and lncRNA-miRNA-mRNA in pancreatic cancer.","Abstract":"Altered expressions of microRNAs (miRNAs) are reported in pancreatic cancer and associate with cancer pathogenesis, apoptosis, and cell growth, thereby functioning as either tumor suppressors or oncogenes. However, the majority of studies focus on defining the regulatory functions of miRNAs, whereas few investigations are directed toward assessing how the miRNA themselves are transcriptionally regulated. In this study, integration of published multi-level expression data and bioinformatics computational approach was used to predict two regulation mechanisms: transcription factors (TF)-miRNA-mRNA regulation and long non-coding RNA(lncRNA)-miRNA-mRNA regulation. To identify differentially expressed mRNAs, miRNAs, and lncRNAs, we integrated microarray expression data in pancreatic cancer tissues and normal tissues. Combination of differentially expressed mRNAs and miRNAs with miRNA-mRNA interactions based on crosslinking and immunoprecipitation followed by high-throughput sequencing (CLIP-Seq) data from StarBas, we constructed miRNA-mRNA regulatory network. Then we constructed two regulatory networks including TF-miRNA-mRNA and lncRNA-miRNA-mRNA based on chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) data from ChIPBase and CLIP-Seq data. A total of 4385 mRNAs, 500 miRNAs, and 21 lncRNAs were differentially expressed, of which, 18 mRNAs and 54 miRNAs are with high confidence. In miRNA-mRNA regulatory network, interrelated miRNAs target 1701 differentially regulated mRNAs. By constructing regulatory network, 19miRNAs including hsa-miR-137, hsa-miR-206, hsa-miR-429, hsa-miR-320d, and hsa-miR-320c are predicted to participate in lncRNA-miRNA-mRNA regulation. Furthermore, 8 miRNAs including hsa-mir-137, hsa-mir-206, hsa-mir-429, hsa-mir-375, hsa-mir-326, hsa-mir-217, hsa-mir-301b, and hsa-mir-184 are predicted to participate in TF-miRNA-mRNA regulation. In an integrated data analysis, we reveal large-scale effects of interrelated miRNAs and provide a model for predicting the mechanism of miRNAs disorder. Our study provides a new insight into understanding the transcriptional regulation of pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-320"}
{"PMID":26807325,"Year":2015,"Title":"Noninvasive urinary miRNA biomarkers for early detection of pancreatic adenocarcinoma.","Abstract":"Currently, the majority of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) present with locally invasive and/or metastatic disease, resulting in five-year survival of less than 5%. The development of an early diagnostic test is, therefore, expected to significantly impact the patient's prognosis. In this study, we successfully evaluated the feasibility of identifying diagnostic cell free microRNAs (miRNAs) for early stage PDAC, through the analysis of urine samples. Using Affymetrix microarrays, we established a global miRNA profile of 13 PDAC, six chronic pancreatitis (CP), and seven healthy (H) urine specimens. Selected differentially expressed miRNAs were subsequently investigated using an independent technique (RT-PCR) on 101 urine samples including 46 PDAC, 29 CP and 26 H. Receiver operating characteristic (ROC) and logistic regression analyses were applied to determine the discriminatory potential of the candidate miRNA biomarkers. Three miRNAs (miR-143, miR-223, and miR-30e) were significantly over-expressed in patients with Stage I cancer when compared with age-matched healthy individuals (P=0.022, 0.035 and 0.04, respectively); miR-143, miR-223 and miR-204 were also shown to be expressed at higher levels in Stage I compared to Stages II-IV PDAC (P=0.025, 0.013 and 0.008, respectively). Furthermore, miR-223 and miR-204 were able to distinguish patients with early stage cancer from patients with CP (P=0.037 and 0.036). Among the three biomarkers, miR-143 was best able to differentiate Stage I (n=6) from healthy (n=26) with area under the curve (AUC) of 0.862 (95% CI 0.695-1.000), with sensitivity (SN) of 83.3% (95% CI 50.0-100.0), and specificity (SP) of 88.5% (95% CI 73.1-100.0). The combination of miR-143 with miR-30e was significantly better at discriminating between these two groups, achieving an AUC of 0.923 (95% CI 0.793-1.000), with SN of 83.3% (95% CI 50.0-100.0) and SP of 96.2% (95% CI 88.5-100.0). In this feasibility study, we demonstrate for the first time the utility of miRNA biomarkers for non-invasive, early detection of PDAC in urine specimens.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-30"}
{"PMID":30458449,"Year":2018,"Title":"Tumor-Secreted Exosomal miR-222 Promotes Tumor Progression via Regulating P27 Expression and Re-Localization in Pancreatic Cancer.","Abstract":"BACKGROUND/AIMS: MicroRNAs (miRNAs) or exosomes have recently been shown to play vital regulatory or communication roles in cancer biology. However, the roles and mechanisms of exosomal miRNAs in pancreatic ductal adenocarcinoma (PDAC) remain unknown. We aimed to investigate the detailed roles and mechanisms of tumor-generated exosomal miRNAs in progression of PDAC. METHODS: miR-222 was identified by miRNA microarray studies in exosomes of PDAC cells, and further analyzed in plasma exosomes of PDAC patients. The regulatory mechanisms of miR-222 were explored by qRT-PCR, WB, dual-luciferase assays and immunofluorescence or confocal analysis. Other biological assays include transwell, xenograft models and so on. RESULTS: miR-222 is significantly high in tumor exosomes or highly invasive PDAC cells. miR-222 could directly regulate p27 to promote cell invasion and proliferation. miR-222 could also activate AKT by inhibiting PPP2R2A expression, thus inducing p27 phosphorylation and cytoplasmic p27 expression to promote cell survival, invasion and metastasis. Expressions of miR-222 and p27 were significantly inversely correlated, and cytoplasmic p27, instead of nuclear p27, was associated with tumor malignancy. miR-222 could be transmitted between PDAC cells via exosome communication, and the exosomal miR-222 communication is functional. Plasma exosomal miR-222 in PDAC patients was high and significantly correlated to tumor size and TNM stage, and was an independent risk factor for PDAC patient survival. CONCLUSION: Tumor-generated exosomes could promote invasion and proliferation of neighboring tumor cells via miR-222 transmission, the plasma exosomal miR-222 plays important roles and may be a useful prognostic maker in PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-222"}
{"PMID":30082912,"Year":2019,"Title":"FGF18, a prominent player in FGF signaling, promotes gastric tumorigenesis through autocrine manner and is negatively regulated by miR-590-5p.","Abstract":"Fibroblast growth factors (FGFs) and their receptors are significant components during fundamental cellular processes. FGF18 plays a distinctive role in modulating the activity of both tumor cells and tumor microenvironment. This study aims to comprehensively investigate the expression and functional role of FGF18 in gastric cancer (GC) and elucidate its regulatory mechanisms. The upregulation of FGF18 was detected in seven out of eleven (63.6%) GC cell lines. In primary GC samples, FGF18 was overexpressed in genomically stable and chromosomal instability subtypes of GC and its overexpression was associated with poor survival. Knocking down FGF18 inhibited tumor formation abilities, induced G1 phase cell cycle arrest and enhanced anti-cancer drug sensitivity. Expression microarray profiling revealed that silencing of FGF18 activated ATM pathway but quenched TGF-beta pathway. The key factors that altered in the related signaling were validated by western blot and immunofluorescence. Meanwhile, treating GC cells with human recombinant FGF18 or FGF18-conditioned medium accelerated tumor growth through activation of ERK-MAPK signaling. FGF18 was further confirmed to be a direct target of tumor suppressor, miR-590-5p. Their expressions showed a negative correlation in primary GC samples and more importantly, re-overexpression of FGF18 partly abolished the tumor-suppressive effect of miR-590-5p. Our study not only identified that FGF18 serves as a novel prognostic marker and a therapeutic target in GC but also enriched the knowledge of FGF-FGFR signaling during gastric tumorigenesis.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-590"}
{"PMID":27630665,"Year":2016,"Title":"Post-transcriptional Regulation of BRCA2 through Interactions with miR-19a and miR-19b.","Abstract":"Breast cancer type 2, early onset susceptibility gene (BRCA2) is a major component of the homologous recombination DNA repair pathway. It acts as a tumor suppressor whose function is often lost in cancers. Patients with specific mutations in the BRCA2 gene often display discrete clinical, histopathological, and molecular features. However, a subset of sporadic cancers has wild type BRCA2 and display defects in the homology-directed repair pathway, which is the hallmark of 'BRCAness.' The mechanisms by which BRCAness arises are not well understood but post-transcriptional regulation of BRCA2 gene expression by microRNAs (miRNAs) may contribute to this phenotype. Here, we examine the post-transcriptional effects that some members of the six-miRNA cluster known as the miR-17/92 cluster have on the abundance of BRCA2's messenger RNA (mRNA) and protein. We discuss two interactions involving the miR-19a and miR-19b members of the cluster and the 3'UTR of BRCA2's mRNA. We investigated these miRNA:mRNA interactions in 15 cell lines derived from pancreatic, breast, colon, and kidney tissue. We show that over-expression of these two miRNAs results in a concomitant decrease of BRCA2's mRNA and protein expression in a subset of the tested cell lines. Additionally, using luciferase reporter assays we identified direct interactions between miR-19a/miR-19b and a miRNA response element (MRE) in BRCA2's 3'UTR. Our results suggest that BRCA2 is subject to a complex post-transcriptional regulatory program that has specific dependencies on the genetic and phenotypic background of cell types.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-92"}
{"PMID":31213904,"Year":2019,"Title":"MiR-193a-3p inhibits pancreatic ductal adenocarcinoma cell proliferation by targeting CCND1.","Abstract":"Background: MicroRNAs (miRNAs) could modulate gene expression at the posttranscriptional level by promoting mRNA degradation or blocking mRNA translation, thus affecting the occurrence and development of cancer. Methods: In this work, qRT-PCR was conducted to detect the expression of miR-193a-3p and CCND1. The ability of cell proliferation was evaluated via CCK-8 assay. Cell apoptosis and cell cycle distribution were detected by flow cytometry. Bioinformatic techniques were employed to research the regulatory relationship between miR-193a-3p and target genes. The relationship between miR-193a-3p and CCND1 was verified via dual-luciferase reporter assays. Results: MiR-193a-3p expression in pancreatic ductal adenocarcinoma (PDAC) tissue was significantly lower than in non-cancerous tissue. After overexpressing miR-193a-3p in PDAC cells, their multiplication ability was significantly inhibited, apoptosis was accelerated, and the cell cycle was blocked in the G1 and G2/M phases. CCND1 was confirmed to have a targeted relationship with miR-193a-3p. Moreover, CCND1 expression was significantly lower in PDAC cells with an overexpression of miR-193a-3p. Conclusions: MiR-193a-3p targeted CCND1 to suppress tumor growth in PDAC cells. MiR-193a-3p may function as a tumor inhibitor in PDAC development, which could offer a promising therapeutic and prognostic strategy for PDAC treatment.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-193"}
{"PMID":25766528,"Year":2015,"Title":"MiR-940 inhibited pancreatic ductal adenocarcinoma growth by targeting MyD88.","Abstract":"BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an almost universally lethal disease. Deregulation or dysfunction of miRNAs contribute to cancer development. The role of miR-940 in PDAC remains unclear. METHODS: The level of miR-940 in PDAC tissues and cell lines was measured by qRT-PCR. MiR-940 was over-expressed by miRNAs mimics transfection and reduced by miRNAs antisense oligonucleotides (ASO) transfection. Cell proliferation was analyzed by MTT assay and cell apoptosis was evaluated by FACS analysis. Targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay. Myeloid differentiation primary response gene (88) (MyD88) protein level was assayed by immunohistochemistry and Western blot analysis. RESULTS: Low miR-940 level and high MyD88 protein level in PDAC tissues were both correlated with low survival rate. Up-regulation of miR-940 inhibited PDAC cell lines growth while down-regulation induced cell growth. The 3' UTR of MyD88 was targeted by miR-940. CONCLUSIONS: Low level of miR-940 and high level of MyD88 in PDAC promoted PDAC cells growth which might be related to the low survival rate of PDAC patients. MiR-940 exerted its effect by targeting MyD88.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-940"}
{"PMID":26516699,"Year":2015,"Title":"Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model.","Abstract":"Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-34"}
{"PMID":28466015,"Year":2017,"Title":"Evaluation of Plasma MicroRNAs as Diagnostic and Prognostic Biomarkers in Pancreatic Adenocarcinoma: miR-196a and miR-210 Could Be Negative and Positive Prognostic Markers, Respectively.","Abstract":"Background. Identifying diagnostic and prognostic biomarkers that could be targeted in the therapy of pancreatic cancer is essential. Objective. Investigations were conducted with respect to plasma miRNA (miR-21, miR-210, miR-155, miR-196a, miR-20a, and miR-25) expression and clinicopathologic factors to evaluate the prognostic value of miRNAs in pancreatic ductal adenocarcinoma (PDAC). Methods. Plasma miRNAs were detected by real-time quantitative PCR, and the association with clinicopathologic factors was subsequently performed by univariate and multivariate analyses. Results. Six miRNAs expressed significantly higher in PDAC patients than in normal individuals were identified. Receiver operating characteristic (ROC) curves were constructed. It was evident that miRNA expression associated with PDAC, lymph node metastasis, serosal infiltration, and comprehensive therapy reached significance for overall survival. High miR-196a expression was associated with poor survival (P = 0.001), whereas high miR-210 expression was significantly associated with improved survival (P = 0.003). Multivariate survival analysis indicated that the miR-210 and miR-196a expression signature, lymph node metastasis, and comprehensive therapy were independent factors affecting overall survival. Conclusions. MiRNA expression profile is distinctive in PDAC. Aberrant expression of certain miRNAs was remarkably involved in shaping the overall survival time, which include miR-196a overexpression and decreased miR-210 expression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-155"}
{"PMID":22245693,"Year":2012,"Title":"Metformin alters the expression profiles of microRNAs in human pancreatic cancer cells.","Abstract":"AIMS: To investigate the effect of metformin on the expression profiles of microRNAs in human pancreatic cancer cells. METHODS: MicroRNAs real-time PCR Array was applied to investigate differentially expressed miRNAs in Sw1990 cells treated with or without metformin. Stem-loop real time RT-PCR was used to confirm the results of the array assay in Sw1990 and Panc-1 cells. The effects of miR-26a on cell growth, apoptosis, invasion and migration abilities were respectively examined by CCK8 assay, Apoptosis assay, Matrigel invasion and migration assay. HMGA1 was proved to be a target of miR-26a by Luciferase reporter assay, Real-time PCR and Western-blotting. RESULTS: Nine miRNAs were significantly up-regulated in metformin treated cells. Metformin up-regulated the expression of miR-26a, miR-192 and let-7c in a dose-dependent manner. Forced expression of miR-26a significantly inhibited cell proliferation, invasion, migration and increased cell apoptosis, whereas knockdown of miR-26a obtained the opposite effect. Furthermore, we demonstrated that HMGA1, an oncogene, is a direct target of miR-26a. Nude mice xenograft models confirmed that metformin up-regulated the level of miR-26a and surpressed the expression of HMGA1 in vivo. CONCLUSION: These observations suggested that modulation of miRNA expression may be an important mechanism underlying the biological effects of metformin.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-26"}
{"PMID":27380024,"Year":2016,"Title":"Specific MAPK-Associated MicroRNAs in Serum Differentiate Pancreatic Cancer from Autoimmune Pancreatitis.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is difficult to distinguish from autoimmune pancreatitis (AIP) because of their clinical and radiological similarities, and therefore simple and minimally invasive surrogate markers for differential diagnosis would be useful. In our previous studies, we identified four microRNAs (miRNAs)-miR-7, miR-34a, miR-181d, and miR-193b -as MAPK-associated microRNAs whose expression was altered significantly with upregulation of the MAPK signaling pathway. Recently it has been reported that these miRNAs could be used as biomarkers in serum samples for accurate diagnosis of pancreatic lesions. The aim of the present study was to evaluate whether these MAPK-associated miRNAs in serum could be used as biomarkers for differentiating PDAC from AIP. We enrolled 69 patients with PDAC, 26 with intraductal papillary mucinous neoplasm (IPMN) and 15 with AIP. The expression of MAPK-associated miRNAs in serum was measured by quantitative real-time PCR. The 2-DeltaCT method was used to quantify the expression of miRNAs, and the data were normalized using spiked-in synthetic cel-miR-39. Patients with PDAC or IPMN showed significantly higher amounts of serum MAPK-associated miRNAs than those with AIP (p<0.009 for miR-7, p<0.002 for miR-34a, p<0.001 for miR-181d, p<0.002 for miR-193b). ROC curve analysis demonstrated that these miRNAs had an area under the ROC curve (AUC) of 0.723-0.882 for differentiation between PDAC or IPMN from AIP. Furthermore, serum miR-181d was significantly associated with the presence of metastasis in patients with PDA (p = 0.014). Serum MAPK-associated miRNAs could be novel noninvasive biomarkers for differentiation between PDAC or IPMN and AIP.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-193"}
{"PMID":29461595,"Year":2018,"Title":"MiR-1271 negatively regulates AKT/MTOR signaling and promotes apoptosis via targeting PDK1 in pancreatic cancer.","Abstract":"OBJECTIVE: Pancreatic cancer (PC) possesses a very poor prognosis, and its pathogenesis is not fully understood. Evidence has suggested that microRNAs play important roles in cancer development and progression, the present study was designed to study the function of miR-1271 in PC. PATIENTS AND METHODS: PC tissues and adjacent normal tissues were collected from 17 patients. MiR-1271 and PDK1 expression were quantified by quantitative reverse-transcriptional polymerase chain reaction (RT-PCR). AKT/MTOR signaling activity and PDK1 protein expression were determined by Western blot. Cell viability and apoptosis were assessed by MTT assay and enzyme-linked immunosorbent assay (ELISA). Luciferase assay was used to verify whether miR-1271 directly targets PDK1. RESULTS: MiR-1271 was significantly down-regulated in PC tissues compared with that in the paired normal adjacent tissue, and its expression was up-regulated dose-dependently upon cisplatin treatment in PC cells. Overexpression of miR-1271 in these cells produced a pro-apoptotic effect, similar to what caused by cisplatin treatment. Moreover, overexpression of miR-1271 inhibited AKT/MTOR signaling, which was due to the targeting relationship between miR-1271 and PDK1. Finally, knockdown of PDK1 exerted a similar effect on apoptosis to that of miR-1271 overexpression. CONCLUSIONS: MiR-1271 is a potent tumor suppressor in PC, its pro-apoptotic function was partially mediated by reduced AKT/MTOR signaling. Targeting miR-1271 may represent an effective strategy for PC treatment.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1271"}
{"PMID":26516699,"Year":2015,"Title":"Changes in microRNA (miRNA) expression during pancreatic cancer development and progression in a genetically engineered KrasG12D;Pdx1-Cre mouse (KC) model.","Abstract":"Differential expression of microRNAs (miRNAs) has been demonstrated in various cancers, including pancreatic cancer (PC). Due to the lack of tissue samples from early-stages of PC, the stage-specific alteration of miRNAs during PC initiation and progression is largely unknown. In this study, we investigated the global miRNA expression profile and their processing machinery during PC progression using the KrasG12D;Pdx1-Cre (KC) mouse model. At 25 weeks, the miRNA microarray analysis revealed significant downregulation of miR-150, miR-494, miR-138, miR-148a, miR-216a, and miR-217 and upregulation of miR-146b, miR-205, miR-31, miR-192, and miR-21 in KC mice compared to controls. Further, expression of miRNA biosynthetic machinery including Dicer, Exportin-5, TRKRA, and TARBP2 were downregulated, while DGCR8 and Ago2 were upregulated in KC mice. In addition, from 10 to 50 weeks of age, stage-specific expression profiling of miRNA in KC mice revealed downregulation of miR-216, miR-217, miR-100, miR-345, miR-141, miR-483-3p, miR-26b, miR-150, miR-195, Let-7b and Let-96 and upregulation of miR-21, miR-205, miR-146b, miR-34c, miR-1273, miR-223 and miR-195 compared to control mice. Interestingly, the differential expression of miRNA in mice also corroborated with the miRNA expression in human PC cell lines and tissue samples; ectopic expression of Let-7b in CD18/HPAF and Capan1 cells resulted in the downregulation of KRAS and MSST1 expression. Overall, the present study aids an understanding of miRNA expression patterns during PC pathogenesis and helps to facilitate the identification of promising and novel early diagnostic/prognostic markers and therapeutic targets.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-150"}
{"PMID":21738581,"Year":2011,"Title":"Tissue and serum microRNAs in the Kras(G12D) transgenic animal model and in patients with pancreatic cancer.","Abstract":"microRNAs (miRs) modulate the expression levels of mRNAs and proteins and can thus contribute to cancer initiation and progression. In addition to their intracelluar function, miRs are released from cells and shed into the circulation. We postulated that circulating miRs could provide insight into pathways altered during cancer progression and may indicate responses to treatment. Here we focus on pancreatic cancer malignant progression. We report that changes in miR expression patterns during progression of normal tissues to invasive pancreatic adenocarcinoma in the p48-Cre/LSL-Kras(G12D) mouse model mirrors the miR changes observed in human pancreatic cancer tissues. miR-148a/b and miR-375 expression were found decreased whereas miR-10, miR-21, miR-100 and miR-155 were increased when comparing normal tissues, premalignant lesions and invasive carcinoma in the mouse model. Predicted target mRNAs FGFR1 (miR-10) and MLH1 (miR-155) were found downregulated. Quantitation of nine microRNAs in plasma samples from patients distinguished pancreatic cancers from other cancers as well as non-cancerous pancreatic disease. Finally, gemcitabine treatment of control animals and p48-Cre/LSL-Kras(G12D) animals with pancreatic cancer caused distinct and up to 60-fold changes in circulating miRs that indicate differential drug effects on normal and cancer tissues. These findings support the significance of detecting miRs in the circulation and suggests that circulating miRs could serve as indicators of drug response.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-155"}
{"PMID":24404812,"Year":2014,"Title":"Alteration of the microRNA expression profile during the activation of pancreatic stellate cells.","Abstract":"OBJECTIVE. Pancreatic stellate cells (PSCs) play a pivotal role in the pancreatic fibrosis associated with chronic pancreatitis and pancreatic cancer. In response to pancreatic injury or inflammation, PSCs are activated to myofibroblast-like cells. MicroRNA (miRNA) is a small RNA, consisting of 17-25 nucleotides, which targets 3'-untranslated region sequences of mRNA. miRNAs regulate a variety of cell functions such as cell proliferation, differentiation, and carcinogenesis. We examined here whether the miRNA expression profiles are altered during the activation of PSCs. MATERIALS AND METHODS. Rat PSCs were isolated from the pancreas tissue of male Wistar rats. PSCs were activated in vitro by culture in serum-containing medium. miRNAs were prepared from quiescent (day 1) PSCs and culture-activated (day 14) PSCs. Agilent's miRNA microarray containing probes for 680 miRNAs was used to identify differentially expressed miRNAs. Ingenuity Pathway Analysis (IPA) was used for the integrated analysis of altered miRNAs. RESULTS. Upon activation, 42 miRNAs were upregulated (>2.0-fold) and 42 miRNAs were downregulated (<0.5-fold). Upregulated miRNAs included miR-31, miR-143, and miR-221. Downregulated miRNAs included miR-126, miR-146a, and miR-150. IPA revealed the most impacted biological processes including cellular development, cellular growth, and cell movement. Interestingly, IPA identified 22 miRNAs affected both in pancreatic cancer and PSC activation. The top network generated by IPA revealed the interactions of altered miRNAs with signaling pathways such as p38 mitogen-activated protein kinase, extracellular-signal-regulated kinase, and Smad2/3. CONCLUSIONS. Our results suggest a novel role of miRNAs in the activation of PSCs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-143"}
{"PMID":29769534,"Year":2018,"Title":"A Five-microRNA Signature for Survival Prognosis in Pancreatic Adenocarcinoma based on TCGA Data.","Abstract":"Novel biomarkers for pancreatic adenocarcinoma are urgently needed because of its poor prognosis. Here, by using The Cancer Genome Atlas (TCGA) RNA-seq data, we evaluated the prognostic values of the differentially expressed miRNAs and constructed a five-miRNA signature that could effectively predict patient overall survival (OS). The Kaplan-Meier overall survival curves of two groups based on the five miRNAs were notably different, showing overall survival in 10.2% and 47.8% at five years for patients in high-risk and low-risk groups, respectively. The ROC curve analysis achieved AUC of 0.775, showing good sensitivity and specificity of the five-miRNA signature model in predicting pancreatic adenocarcinoma patient survival risk. The functional enrichment analysis suggested that the target genes of the miRNA signature may be involved in various pathways related to cancer, including PI3K-Akt, TGF-beta, and pluripotent stem cell signaling pathways. Finally, we analyzed expression of the five specific miRNAs in the miRNA signature, and validated the reliability of the results in 20 newly diagnosed pancreatic adenocarcinoma patients using qRT-PCR. The expression results of qRT-PCR were consistent with the TCGA results. Taken together, these findings suggested that the five-miRNA signature (hsa-miR-203, hsa-miR-424, hsa-miR-1266 hsa-miR-1293, and hsa-miR-4772) could be used as a prognostic marker for pancreatic adenocarcinoma.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-424"}
{"PMID":25520858,"Year":2014,"Title":"MicroRNAs in stool samples as potential screening biomarkers for pancreatic ductal adenocarcinoma cancer.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) accounts for approximately 90-95% exocrine malignant tumors of the pancreas. The high prevalence of metastasis and the difficulty of early diagnosis lead to a dismal prognosis. MicroRNAs (miRNAs) play a critical role in extensive biological processes. The purpose of this study was to evaluate the feasibility of stool miRNAs as novel biomarker for PDAC screening. MiRNAs were extracted from clinical specimens which included cancer and matched adjacent benign pancreatic tissues of 30 PDAC patients, pancreatic juice of 20 from the 30 PDAC patients and 10 chronic pancreatitis (CP) patients, stool samples of the 30 PDAC patients, the 10 CP patients and 15 healthy volunteers. Relative expression of a panel of 5 dysregulated miRNAs (miR-21, miR-155, miR-196a, miR-216 and miR-217) was analyzed with qRT-PCR. Receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosing value of stool miRNAs in PDAC patients. The study showed that our methods of extracting and detecting miRNAs from pancreatic juice and stool specimens had high reproducibility. Compared to matched adjacent benign pancreatic tissues and pancreatic juice of CP patients, the expression of miR-21 (P = 0.0021 and P = 0.0027) as well as miR-155 (P = 0.0087 and P = 0.0067) was significantly higher and the expression of miR-216 (P < 0.0001 and P = 0.0044) was significantly lower in primary tumor tissues and pancreatic juice of PDAC patients. PDAC patients had a significantly higher stool miR-21 and miR-155 (P = 0.0049 and P = 0.0112) and lower miR-216 level (P = 0.0002) compared to normal controls. The same results were obtained in the expression levels of stool miR-21, miR-155 and miR-216 between PDAC and CP patients (P = 0.0337, P = 0.0388 and P = 0.0117, respectively). Receiver operating characteristic (ROC) analysis by using stool miRNAs expression indicated that combination of miR-21 and miR-155 had best sensitivity of 93.33% while the combination of miR-21, miR-155 and miR-216 would be best for detecting and screening PDAC with area under the curve (AUC) of 0.8667 (95% CI: 0.7722-0.9612) and a better balance of sensitivity and specificity (83.33% vs. 83.33%). Our data indicate that miRNAs could be extracted and detected from pancreatic juice and stool efficiently and reproducibly. MiR-21, miR-155 and miR-216 in stool have the potential of becoming biomarkers for screening PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-217"}
{"PMID":23338123,"Year":2013,"Title":"Highly lymphatic metastatic pancreatic cancer cells possess stem cell-like properties.","Abstract":"Cancer stem cells are thought to be the origin of tumor metastasis. However, evidence of cancer stem cells as the source of lymphatic metastasis in pancreatic cancer is not clear. In this study, we examined the stem cell-like properties of the highly lymphatic metastatic pancreatic cancer cells BxPC-3-LN. Compared with the parental BxPC-3 cells, the BxPC-3-LN cells showed stem cell-like properties, including high lymphatic metastasis potential, self-renewal ability and chemoresistance. In addition, the BxPC-3-LN cells also expressed higher levels of sonic hedgehog and migrating cancer stem cell surface markers (CD133 and CXCR4) compared to the parental BxPC-3 cells. The growth of BxPC-3-LN cells was significantly inhibited by gemcitabine combined with the sonic hedgehog inhibitor cyclopamine. The BxPC-3-LN cells expressed lower levels of let-7, miR-34, miR-107, miR-125, miR-128, miR-130, miR-132 and miR-141 than the parental BxPC-3 cells detected by microRNA PCR array, which were reported to have close relation to stem cell factors. This study provides evidence that cancer stem cells are the major sources of pancreatic cancer lymphatic metastasis, and microRNAs may regulate lymphatic metastasis in pancreatic cancer through modulating cancer stem cells.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-125"}
{"PMID":24575833,"Year":2014,"Title":"A microRNA meta-signature for pancreatic ductal adenocarcinoma.","Abstract":"Due to its aggressive and late presentation, there is an urgent need for novel and reliable biomarkers for the diagnosis and prognostication of pancreatic ductal adenocarcinoma (PDAC). MiRNAs have been extensively profiled in PDAC tissues, biopsies, blood samples and other biofluids and their expression levels compared to normal and chronic pancreatitis (CP) specimens in order to identify the most relevant candidates. Consolidation of these activities has not been attempted until now. The evaluated meta-review by Ma et al. helps to define the use of miRNAs as biomarkers for detecting this tumor-type and predicting survival outcomes in PDAC. Based on frequency and consistency between microarray studies, they identified a miRNA meta-signature for recognising PDAC: upregulation of miR-21, 23a, 31, 100, 143, 155, and 221; with downregulation of miR-148a, 217 and 375. Furthermore, they validated high miR-21, high miR-31 and low miR-375 tumoural expression as independently prognostic for poor overall-survival (OS; n = 70).","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-155"}
{"PMID":23900458,"Year":2013,"Title":"MicroRNA-29a induces resistance to gemcitabine through the Wnt/beta-catenin signaling pathway in pancreatic cancer cells.","Abstract":"Although we studied previously the mechanisms of resistance of pancreatic cancer cells to gemcitabine (GEM), prediction of the response to GEM remains unsatisfactory. The aim of this study was to investigate the relationship between miR-29a expression and the response to GEM in pancreatic cancer cells. Changes in the growth-inhibitory effect of pancreatic cancer cells (MIAPaCa-2, PSN-1, BxPC-3 and Panc-1) to GEM were examined after overexpression or suppression of miR-29a. We also examined the effect of miR-29a on the Wnt/beta-catenin signaling pathway and investigated whether the altered growth-inhibitory effect by miR-29a suppression was weakened after the addition of Wnt3a, a Wnt/beta-catenin signaling activator. MIAPaCa-2 and PSN-1 cells transfected with anti-miR-29a showed significantly lower resistance to GEM. In the anti-miR-29a-transfected cells, GEM induced significantly larger numbers of apoptotic cells and S phase accumulation compared to control cells, demonstrated by Annexin V assay and flow cytometric analysis of the cell cycle, respectively. The transfected cells showed overexpression of putative target molecules including Dkk1, Kremen2 and sFRP2 and lower activation of the Wnt/beta-catenin signaling pathway. The addition of Wnt3a weakened the augmented growth-inhibitory effect of anti-miR-29a transfection. Our findings suggest that miR-29a expression correlates significantly with the growth-inhibitory effect of GEM and that activation of the Wnt/beta-catenin signaling pathway mediated the miR-29a-induced resistance to GEM in pancreatic cancer cell lines.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-29"}
{"PMID":27541609,"Year":2017,"Title":"miR-216 and miR-217 expression is reduced in transgenic mouse models of pancreatic adenocarcinoma, knockout of miR-216/miR-217 host gene is embryonic lethal.","Abstract":"Mice harboring a G12D activating Kras mutation are among the most heavily studied models in the field of pancreatic adenocarcinoma (PDAC) research. miRNAs are differentially expressed in PDAC from patients and mouse models of PDAC. To better understand the relationship that Kras activation has on miRNA expression, we profiled the expression of 629 miRNAs in RNA isolated from the pancreas of control, young, and old P48(+/Cre);LSL-KRAS(G12D) as well as PDX-1-Cre;LSL-KRAS(G12D) mice. One hundred of the differentially expressed miRNAs had increased expression in the advanced disease (old) P48(+/Cre);LSL-KRAS(G12D) compared to wild-type mice. Interestingly, the expression of three miRNAs, miR-216a, miR-216b, and miR-217, located within a approximately 30-kbp region on 11qA3.3, decreased with age (and phenotype severity) in these mice. miR-216/-217 expression was also evaluated in another acinar-specific ELa-Kras(G12D) mouse model and was downregulated as well. As miR-216/-217 are acinar enriched, reduced in human PDAC and target KRAS, we hypothesized that they may maintain acinar differentiation or represent tumor suppressive miRNAs. To test this hypothesis, we deleted a 27.9-kbp region of 11qA3.3 containing the miR-216/-217 host gene in the mouse's germ line. We report that germ line deletion of this cluster is embryonic lethal in the mouse. We estimate that lethality occurs shortly after E9.5. qPCR analysis of the miR-216b and miR-217 expression in the heterozygous animals showed no difference in expression, suggesting haplosufficiency by some type of compensatory mechanism. We present the differential miRNA expression in Kras(G12D) transgenic mice and report lethality from deletion of the miR-216/-217 host gene in the mouse's germ line.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-217"}
{"PMID":16461460,"Year":2006,"Title":"A microRNA expression signature of human solid tumors defines cancer gene targets.","Abstract":"Small noncoding microRNAs (miRNAs) can contribute to cancer development and progression and are differentially expressed in normal tissues and cancers. From a large-scale miRnome analysis on 540 samples including lung, breast, stomach, prostate, colon, and pancreatic tumors, we identified a solid cancer miRNA signature composed by a large portion of overexpressed miRNAs. Among these miRNAs are some with well characterized cancer association, such as miR-17-5p, miR-20a, miR-21, miR-92, miR-106a, and miR-155. The predicted targets for the differentially expressed miRNAs are significantly enriched for protein-coding tumor suppressors and oncogenes (P < 0.0001). A number of the predicted targets, including the tumor suppressors RB1 (Retinoblastoma 1) and TGFBR2 (transforming growth factor, beta receptor II) genes were confirmed experimentally. Our results indicate that miRNAs are extensively involved in cancer pathogenesis of solid tumors and support their function as either dominant or recessive cancer genes.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-20"}
{"PMID":26505678,"Year":2015,"Title":"Plasma microRNA profiles: identification of miR-744 as a novel diagnostic and prognostic biomarker in pancreatic cancer.","Abstract":"BACKGROUND: This study aims to explore novel microRNAs in plasma for screening cancer and predicting clinical outcomes in pancreatic cancer (PCa) patients using a microRNA array-based approach. METHODS: We used the Toray 3D-Gene microRNA array-based approach to compare plasma levels between PCa patients and healthy volunteers. RESULTS: (1) Six oncogenic microRNAs (miR-615-5p, -744, -575, -557, -675, and -550a) with high expression in plasma were selected. (2) By quantitative RT-PCR using plasma samples from 94 PCa patients and 68 healthy volunteers, a significantly higher level of plasma miR-744 in PCa patients than in healthy volunteers was validated in small-scale analysis (P=0.0038), two independent cohort analyses, and large-scale analysis (P<0.0001, AUC 0.8307). (3) miR-744 expression was significantly higher in PCa tissues (P=0.0069) and PCa cell lines (P=0.0074) than in normal tissues and fibroblasts, respectively. Preoperative plasma level of miR-744 was significantly reduced in postoperative samples (P=0.0063). (4) A high level of plasma miR-744, which was correlated with lymph node metastasis (P=0.0407) and recurrences (P=0.0376), was an independent poor prognostic factor of PCa patients after pancreatectomy (P=0.0007, HR 21.2 (3.17-436)). Furthermore, a high level of plasma miR-744 contributed to poorer progression-free survival of non-operable PCa patients who underwent gemcitabine-based chemotherapy (P=0.0533). Overexpression of miR-744 in PCa cells induced significant chemoresistance to gemcitabine in vitro. CONCLUSIONS: Plasma miR-744 might be useful biomarker for screening PCa, monitoring, and predicting poor prognosis and chemoresistance in PCa patients.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-575"}
{"PMID":25906450,"Year":2015,"Title":"Postoperative prognosis prediction of pancreatic cancer with seven microRNAs.","Abstract":"OBJECTIVES: The aim of this study was to investigate microRNAs related to postoperative prognosis of pancreatic cancer by applying microarray analysis to stored surgical specimens. METHODS: We retrospectively analyzed the relationship between microRNA expression and postoperative survival of pancreatic cancer patients in Samsung Medical Center. After the correlation of microRNA expression between paraffin-embedded and fresh-frozen specimens was confirmed, we applied NanoString nCounter system to formalin fixed paraffin-embedded surgical specimens between 1995 September and 2010 June. RESULTS: Paired fresh and paraffin-embedded samples from 9 patients showed a high correlation (correlation coefficient > 0.91). Among 734 microRNAs, 7 microRNAs were found to be related to postoperative overall survival of 221 pancreatic cancer patients: hsa-miR-99a, hsa-miR-150, hsa-miR-194, hsa-miR-375, hsa-miR-664, hsa-miR-342-3p, and hsa-miR-487b (P < 0.01). The prognostic microRNA signature was consistent after adjustment of clinical parameters: resection status, stages, age, sex, adjuvant treatment, pathological differentiation and postoperative carbohydrate antigen 19-9 levels. CONCLUSIONS: We found a prediction model for postoperative prognosis of pancreatic cancer using 7 microRNA expression patterns from archived formalin-fixed paraffin-embedded surgical specimens. The methods for microRNA detection and new microRNAs detected in this study provide new insights for new research of surgically resected pancreatic cancer samples and microRNAs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-342"}
{"PMID":25894267,"Year":2015,"Title":"[miRNA-192, miRNA-21 and miRNA-200: new pancreatic cancer markers in diabetic patients?].","Abstract":"INTRODUCTION: Newly-onset diabetes mellitus (DM) in middle-aged and older people may be an early symptom of pancreatic cancer (PC). However, sensitive markers for PC are still missing. MicroRNAs (miRNAs) play an important role in a cell response regulation. Significant changes in miRNA expressions were observed in cancers. Our goal was to compare expressions of selected miRNAs in patients with PC, DM and controls. METHODS: We enrolled 74 patients with PC (42/32, with/without DM), 29 type 2 diabetic patients and 17 controls. MicroRNA was determined in serum of all examined subjects. In 9 patients with PC the tumor was resected subsequently and after 3 months the measurements were repeated. We analyzed the expressions of 8 miRNAs that we had identified in a previous pilot study (miR-21, miR-30, miR-191, miR-192, miR-196, miR-200, miR-423, miR-454). RESULTS: MicroRNA expressions were significantly higher in patients with PC than in DM and controls: miR-192: 1.6 (1.2 to 2.0) vs 0.3 (0.2-0.4) vs 0.3 (0.2 to 0.5), p < 0.00001; miR-21: 1.4 (1.2-1.7) vs 0.3 (0.2 to 0.5) vs 0.5 (from 0.4 to 0.7), p < 0.00001, miR-200: 1.6 (1.1 to 2.3) vs 0.3 (0.3-0.4) vs 0.3 (0.2 to 0.4), p < 0.00001. No difference was observed between DM and controls, as well as between diabetic and non-diabetic patients within the PC group. There were no significant differences in miRNA expressions in 9 patients after pancreatic surgery. But there were significant interindividual differences. CONCLUSION: Our data shows that miR-21, miR-192 and miR-200 could be used as new diagnostic markers for pancreatic cancer. A dynamics of these miRNAs could serve as a prognostic marker in patients after cancer removal. Futher prospective studies with newly-onset diabetic patients with no signs of malignancy will be needed to validate if suggested miRNAs could be used as early markers as well.","Language":"cze","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-192"}
{"PMID":26662432,"Year":2015,"Title":"Reduced miRNA-218 expression in pancreatic cancer patients as a predictor of poor prognosis.","Abstract":"microRNA-218 (miR-218) is a vertebrate-specific miRNA that plays a crucial role in tumorigenesis and tumor progression. This study analyzed the miR-218 expression level and clinical significance in pancreatic cancer. One hundred and seven pairs of pancreatic cancer and adjacent normal tissues were analyzed by quantitative reverse-transcriptase polymerase chain reaction. The correlation between miR-218 expression and clinicopathological characters was determined by the two-sample Student t-test. The survival correlations were analyzed by the Kaplan-Meier method and Cox proportional hazards model. The relative expression of miR-218 in pancreatic cancer tissues (2.63 +/- 1.59) was significantly lower than that in matched noncancerous pancreatic tissues (6.52 +/- 2.50, P < 0.001). The low expression of miR-218 in the pancreatic cancer tissues were strongly correlated with the TNM classification (P = 0.02), distant metastasis (P = 0.001), and tumor differentiation (P = 0.003). The low level of miR-218 expression was significantly correlated with the shorter overall survival time of pancreatic cancer patients (5-year overall survival rate: 7.5 vs 34.9%; log-rank test: P < 0.001). Multivariate analyses confirmed that a low level of miR-218 expression was an independent predictor of poor prognosis in pancreatic cancer patients (Hazard ratio: 7.24; 95% confidence interval: 2.01-18.28; P = 0.007). Our findings suggested a significant downregulation in the expression of miR-218; this might have considerable potential value in the prognosis for pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-218"}
{"PMID":22114139,"Year":2012,"Title":"MicroRNA alterations of pancreatic intraepithelial neoplasias.","Abstract":"PURPOSE: MicroRNA (miRNA) alterations are likely to contribute to the development of pancreatic cancer and may serve as markers for the early detection of pancreatic neoplasia. EXPERIMENTAL DESIGN: To identify the miRNA alterations that arise during the development of pancreatic cancer, we determined the levels of 735 miRNAs in 34 pancreatic intraepithelial neoplasias (PanIN) and 15 normal pancreatic duct samples isolated by laser capture microdissection using TaqMan miRNA microarrays. Differential expression of selected miRNAs was confirmed by FISH analysis and by quantitative real-time reverse transcription PCR (qRT-PCR) analysis of selected candidate miRNAs in an independent set of PanIN and normal duct samples. RESULTS: We identified 107 aberrantly expressed miRNAs in different PanIN grades compared with normal pancreatic duct samples and 35 aberrantly expressed miRNAs in PanIN-3 lesions compared with normal pancreatic duct samples. These differentially expressed miRNAs included those that have been previously identified as differentially expressed in pancreatic ductal adenocarcinomas (PDAC; including miR-21, miR-200a/b/c, miR-216a/b, miR-217, miR-146a, miR-155, miR-182, miR-196b, miR-203, miR-222, miR-338-3p, miR-486-3p, etc.) as well as miRNAs not previously described as differentially expressed in these lesions (miR-125b, miR-296-5p, miR-183*, miR-603, miR-625/*, miR-708, etc.). miR-196b was the most selectively differentially expressed miRNA in PanIN-3 lesions. CONCLUSIONS: Many miRNAs undergo aberrant expression in PanIN lesions and are likely to be important in the development of PDAC. The miRNAs, such as miR-196b, whose expression is limited to PanIN-3 lesions or pancreatic cancers could be useful as diagnostic markers.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-125"}
{"PMID":19407485,"Year":2009,"Title":"Epigenetic silencing of MicroRNA miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer.","Abstract":"Aberrant expression of microRNAs (miRNAs) has emerged as an important hallmark of cancer. However, the putative mechanisms regulating miRNAs per se are only partially known. It is well established that many tumor suppressor genes in human cancers are silenced by chromatin alterations, including promoter methylation and histone deacetylation. We postulated that miRNAs undergo similar epigenetic inactivation in pancreatic cancer. Two human pancreatic cancer cell lines - MiaPACA-2 and PANC-1 - were treated with the demethylating agent, 5-aza-2'-deoxycytidine (5-Aza-dC) or the histone deacetylase inhibitor, trichostatin A, as well as the combination of the two. Expression of miRNAs in control and treated cell lines was assessed using a custom microarray platform. Fourteen miRNAs were upregulated two-fold or greater in each of the cell lines following exposure to both chromatin-modifying agents, including 5 that were in common (miR-107, miR-103, miR-29a, miR-29b, and miR-320) to both MiaPACA-2 and PANC-1. The differential overexpression of miR-107 in the treated cancer cell lines was confirmed by Northern blot assays. Methylation-specific PCR assays for assessment of CpG island methylation status in the 5' promoter region of the miR-107 primary transcript demonstrated complete loss of methylation upon exposure to 5-Aza-dC. Enforced expression of miR-107 in MiaPACA-2 and PANC-1 cells downregulated in vitro growth, and this was associated with repression of the putative miR-107 target, cyclin-dependent kinase 6, thereby providing a functional basis for the epigenetic inactivation of this miRNA in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-107"}
{"PMID":22188669,"Year":2012,"Title":"MicroRNAs associated with mitogen-activated protein kinase in human pancreatic cancer.","Abstract":"Aberrant expression of microRNAs (miRNA) is associated with phenotypes of various cancers, including pancreatic cancer. However, the mechanism of the aberrant expression is largely unknown. Activation of the mitogen-activated protein kinase (MAPK) signaling pathway plays a crucial role in gene expression related to the malignant phenotype of pancreatic cancer. Hence, we studied the role of MAPK in the aberrant expression of miRNAs in pancreatic cancer cells. The alterations in expression of 183 miRNAs induced by activation or inactivation of MAPK were assayed in cultured pancreatic cancer cells and HEK293 cells by means of the quantitative real-time PCR method. We found that four miRNAs, namely, miR-7-3, miR-34a, miR-181d, and miR-193b, were preferentially associated with MAPK activity. Among these miRNAs, miR-7-3 was upregulated by active MAPK, whereas the others were downregulated. Promoter assays indicated that the promoter activities of the host genes of miR-7-3 and miR-34a were both downregulated by alteration in MAPK activity. Exogenous overexpression of the MAPK-associated miRNAs had the effect of inhibition of the proliferation of cultured pancreatic cancer cells; miR-193b was found to exhibit the most remarkable inhibition. A search for target genes of miR-193b led to identification of CCND1, NT5E, PLAU, STARD7, STMN1, and YWHAZ as the targets. Translational suppression of these genes by miR-193b was confirmed by reporter assay. These results indicate that activation of MAPK may play a significant role in aberrant expression of miRNAs and their associated phenotypes in pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-193"}
{"PMID":28813705,"Year":2017,"Title":"The Lncrna-TUG1/EZH2 Axis Promotes Pancreatic Cancer Cell Proliferation, Migration and EMT Phenotype Formation Through Sponging Mir-382.","Abstract":"BACKGROUND/AIMS: Pancreatic carcinoma (PC) is the one of the most common and malignant cancers worldwide. LncRNA taurine upregulated gene 1 (TUG1) was initially identified as a transcript upregulated by taurine, and the abnormal expression of TUG1 has been reported in many cancers. However, the biological role and molecular mechanism of TUG1 in PC still needs further investigation. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to measure the expression of TUG1 in PC cell lines and tissues. MTT and colony formation assays were used to measure the effect of TUG1 on cell proliferation. A wound healing assay, transwell assay and western blot assay were employed to determine the effect of TUG1 on cell migration and the epithelial mesenchymal transition (EMT) phenotype. RNA-binding protein immunoprecipitation (RIP) and a biotin-avidin pulldown system were performed to confirm the interaction between miR-328 and TUG1. A gene expression array analysis using clinical samples and RT-qPCR suggested that enhancer of zeste homolog 2 (EZH2) was a target of miR-382 in PC. RESULTS: In this study, we reported that TUG1 was overexpressed in PC tissues and cell lines, and high expression of TUG1 predicted poor prognosis. Further experiments revealed that overexpressed TUG1 promoted cell proliferation, migration and contributed to EMT formation, whereas silenced TUG1 led to opposing results. Additionally, luciferase reporter assays, an RIP assay and an RNA-pulldown assay demonstrated that TUG1 could competitively sponge miR-382 and thereby regulate EZH2. CONCLUSION: Collectively, these findings revealed that TUG1 functions as an oncogenic lncRNA that promotes tumor progression, at least partially, by functioning as an endogenous 'sponge' and competing for miR-382 binding to the miRNA target EZH2.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-328"}
{"PMID":26683934,"Year":2015,"Title":"High Expression of MicroRNA-196a Indicates Poor Prognosis in Resected Pancreatic Neuroendocrine Tumor.","Abstract":"There is limited data on miRNA expression in pancreatic neuroendocrine tumors (PanNETs). In this study, we aimed to identify miRNAs that could be potential prognostic biomarkers of PanNETs in patients who underwent curative surgery. For miRNA target screening, 2 primary PanNETs and corresponding liver metastases were screened for miRNA expression by the NanoString nCounter analysis. Candidate miRNAs were selected by >/=2-fold difference of expression between metastatic versus primary tumor. For miRNA target validation, quantitative real-time PCR was performed for candidate miRNAs on 37 PanNETs and matched nonneoplastic pancreata, and the miRNA levels were correlated with the clinicopathological features and patient survival data. Eight miRNAs (miRNA-27b, -122, -142-5p, -196a, -223, -590-5p, -630, and -944) were selected as candidate miRNAs. Only miR-196a level was significantly associated with stage, and mitotic count. When PanNETs were stratified into high (n = 10) and low (n = 27) miRNA-196a expression groups, miRNA-196a-high PanNETs were significantly associated with advanced pathologic T stage (50.0% vs 7.4%), N stage (50.0% vs 3.7%), higher mitotic counts (60.0% vs 3.7%), and higher Ki-67-labeling indices (60.0% vs 22.2%). In addition, high miRNA-196a expression was significantly associated with decreased overall survival (P = 0.046) and disease-free survival (P < 0.001) during a median follow-up of 37.9 months with the hazard ratio for recurrence of 16.267 (95% confidence interval = 1.732-153.789; P = 0.015). MiRNA-196a level may be a promising prognostic marker of recurrence in resected PanNETs, although further experimental investigation would be required.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-196"}
{"PMID":30654191,"Year":2019,"Title":"The Modulatory Role of MicroRNA-873 in the Progression of KRAS-Driven Cancers.","Abstract":"KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3' UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-873"}
{"PMID":28813705,"Year":2017,"Title":"The Lncrna-TUG1/EZH2 Axis Promotes Pancreatic Cancer Cell Proliferation, Migration and EMT Phenotype Formation Through Sponging Mir-382.","Abstract":"BACKGROUND/AIMS: Pancreatic carcinoma (PC) is the one of the most common and malignant cancers worldwide. LncRNA taurine upregulated gene 1 (TUG1) was initially identified as a transcript upregulated by taurine, and the abnormal expression of TUG1 has been reported in many cancers. However, the biological role and molecular mechanism of TUG1 in PC still needs further investigation. METHODS: Quantitative real-time PCR (qRT-PCR) was performed to measure the expression of TUG1 in PC cell lines and tissues. MTT and colony formation assays were used to measure the effect of TUG1 on cell proliferation. A wound healing assay, transwell assay and western blot assay were employed to determine the effect of TUG1 on cell migration and the epithelial mesenchymal transition (EMT) phenotype. RNA-binding protein immunoprecipitation (RIP) and a biotin-avidin pulldown system were performed to confirm the interaction between miR-328 and TUG1. A gene expression array analysis using clinical samples and RT-qPCR suggested that enhancer of zeste homolog 2 (EZH2) was a target of miR-382 in PC. RESULTS: In this study, we reported that TUG1 was overexpressed in PC tissues and cell lines, and high expression of TUG1 predicted poor prognosis. Further experiments revealed that overexpressed TUG1 promoted cell proliferation, migration and contributed to EMT formation, whereas silenced TUG1 led to opposing results. Additionally, luciferase reporter assays, an RIP assay and an RNA-pulldown assay demonstrated that TUG1 could competitively sponge miR-382 and thereby regulate EZH2. CONCLUSION: Collectively, these findings revealed that TUG1 functions as an oncogenic lncRNA that promotes tumor progression, at least partially, by functioning as an endogenous 'sponge' and competing for miR-382 binding to the miRNA target EZH2.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-382"}
{"PMID":25607660,"Year":2015,"Title":"A genome-wide investigation of microRNA expression identifies biologically-meaningful microRNAs that distinguish between high-risk and low-risk intraductal papillary mucinous neoplasms of the pancreas.","Abstract":"BACKGROUND: Intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursors. Differentiating between high-risk IPMNs that warrant surgical resection and low-risk IPMNs that can be monitored is a significant clinical problem, and we sought to discover a panel of mi(cro)RNAs that accurately classify IPMN risk status. METHODOLOGY/PRINCIPAL FINDINGS: In a discovery phase, genome-wide miRNA expression profiling was performed on 28 surgically-resected, pathologically-confirmed IPMNs (19 high-risk, 9 low-risk) using Taqman MicroRNA Arrays. A validation phase was performed in 21 independent IPMNs (13 high-risk, 8 low-risk). We also explored associations between miRNA expression level and various clinical and pathological factors and examined genes and pathways regulated by the identified miRNAs by integrating data from bioinformatic analyses and microarray analysis of miRNA gene targets. Six miRNAs (miR-100, miR-99b, miR-99a, miR-342-3p, miR-126, miR-130a) were down-regulated in high-risk versus low-risk IPMNs and distinguished between groups (P<10-3, area underneath the curve (AUC) = 87%). The same trend was observed in the validation phase (AUC = 74%). Low miR-99b expression was associated with main pancreatic duct involvement (P = 0.021), and serum albumin levels were positively correlated with miR-99a (r = 0.52, P = 0.004) and miR-100 expression (r = 0.49, P = 0.008). Literature, validated miRNA:target gene interactions, and pathway enrichment analysis supported the candidate miRNAs as tumor suppressors and regulators of PDAC development. Microarray analysis revealed that oncogenic targets of miR-130a (ATG2B, MEOX2), miR-342-3p (DNMT1), and miR-126 (IRS-1) were up-regulated in high- versus low-risk IPMNs (P<0.10). CONCLUSIONS: This pilot study highlights miRNAs that may aid in preoperative risk stratification of IPMNs and provides novel insights into miRNA-mediated progression to pancreatic malignancy. The miRNAs identified here and in other recent investigations warrant evaluation in biofluids in a well-powered prospective cohort of individuals newly-diagnosed with IPMNs and other pancreatic cysts and those at increased genetic risk for these lesions.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-99"}
{"PMID":25017900,"Year":2014,"Title":"Sulforaphane, quercetin and catechins complement each other in elimination of advanced pancreatic cancer by miR-let-7 induction and K-ras inhibition.","Abstract":"Pancreatic ductal adenocarcinoma (PDA) has the worst prognosis of all malignancies, and current therapeutic options do not target cancer stem cells (CSCs), which may be the reason for the extreme aggressiveness. The dietary agents sulforaphane and quercetin enriched e.g., in broccoli, and the main and best studied green tea catechin EGCG hold promise as anti-CSC agents in PDA. We examined the efficacy of additional catechins and the combination of these bioactive agents to stem cell features and miRNA signaling. Two established and one primary PDA cell line and non-malignant pancreatic ductal cells were used. Whereas each agent strongly inhibited colony formation, the catechins ECG and CG were more effective than EGCG. A mixture of green tea catechins (GTCs) significantly inhibited viability, migration, expression of MMP-2 and -9, ALDH1 activity, colony and spheroid formation and induced apoptosis, but the combination of GTCs with sulforaphane or quercetin was superior. Following treatment with bioactive agents, the expression of miR-let7-a was specifically induced in cancer cells but not in normal cells and it was associated with K-ras inhibition. These data demonstrate that sulforaphane, quercetin and GTC complement each other in inhibition of PDA progression by induction of miR-let7-a and inhibition of K-ras.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"let-7-"}
{"PMID":28968959,"Year":2017,"Title":"MiR-187 overexpression inhibits cervical cancer progression by targeting HPV16 E6.","Abstract":"Aberrantly expressed microRNAs contribute to the initiation and progression of human cancer. MiRNA-187 has been reported in nasopharyngeal, renal, pancreatic, prostate, and esophageal cancer, and acts as a tumor suppressor or oncogene. However, the underlying function of miRNA-187 in cervical cancer remains largely unexplored. In the present study, we demonstrated significantly miRNA-187 down-regulation in cervical cancer tissues and cell lines compared to their normal counterparts. Kaplan-Meier analysis revealed that decreased miRNA-187 was closely associated with shorter overall survival and relapse-free survival. Gain- and loss-of-function studies showed that miRNA-187 suppressed cervical cancer cell proliferation, migration, and invasion, and promoted cervical cancer cell apoptosis. Furthermore, luciferase reporter assay determined that human papillomavirus 16 E6 was a direct functional target of miRNA-187. Taken together, our findings indicate the essential role of miRNA-187 in suppressing cervical cancer progression and indicate a novel link between miRNA-187 and human papillomavirus 16 E6 in cervical cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-187"}
{"PMID":29156694,"Year":2017,"Title":"PDAC-derived exosomes enrich the microenvironment in MDSCs in a SMAD4-dependent manner through a new calcium related axis.","Abstract":"Tumor genetics and escape from immune surveillance concur in the poor prognosis of PDAC. In this study an experimental model was set up to verify whether SMAD4, deleted in about 55% PDAC and associated with poor prognosis, is involved in determining immunosuppression through Exosomes (Exo). Potential mechanisms and mediators underlying SMAD4-dependent immunosuppression were evaluated by studying intracellular calcium (Fluo-4), Exo-miRNAs (microarray) and Exo-proteins (SILAC). Two PDAC cell lines expressing (BxPC3-SMAD4+) or not-expressing (BxPC3) SMAD4 were used to prepare Exo-enriched conditioned media, employed in experiments with blood donors PBMCs. Exo expanded myeloid derived suppressor cells (gMDSC and mMDSC, flow cytometry) and altered intracellular calcium fluxes in an SMAD4 dependent manner. BxPC3-SMAD4+, but mainly BxPC3 Exo, increased calcium fluxes of PBMCs (p = 0.007) and this increased intracellular calcium trafficking characterized mMDSCs. The analysis of de-regulated Exo-miRNAs and transfection experiments revealed hsa-miR-494-3p and has-miR-1260a as potential mediators of SMAD4-associated de-regulated calcium fluxes. Eleven main biological processes were identified by the analysis of SMAD4-associated de-regulated Exo-proteins, including translation, cell adhesion, cell signaling and glycolysis. A reverse Warburg effect was observed by treating PBMCs with PDAC-derived Exo: BxPC3 Exo induced a higher glucose consumption and lactate production than BxPC3-SMAD4+ Exo. CONCLUSION: PDAC-derived Exo from cells with, but mainly from those without SMAD4 expression, create an immunosuppressive myeloid cell background by increasing calcium fluxes and glycolysis through the transfer of SMAD4-related differentially expressed miRNAs and proteins.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1260"}
{"PMID":25635996,"Year":2015,"Title":"MiR-1178 promotes the proliferation, G1/S transition, migration and invasion of pancreatic cancer cells by targeting CHIP.","Abstract":"CHIP, a co-chaperone protein that interacts with Hsc/Hsp70, has been shown to be under-expressed in pancreatic cancer cells and has demonstrated a potential tumor suppressor property. Nevertheless, the underlying mechanisms of CHIP regulation in pancreatic cancer cells remain unknown. In this study, we found that miR-1178 decreased the translation of the CHIP protein by targeting the 3'-UTR region. We observed that over-expression of miR-1178 facilitated the proliferation, G1/S transition, migration and invasion of pancreatic cancer cells. Conversely, the inhibition of miR-1178 expression significantly suppressed these phenotypes. Furthermore, CHIP over-expression abrogated miR-1178-induced cell proliferation and invasion. Our data suggest that miR-1178 acts as an oncomiR in pancreatic cancer cells by inhibiting CHIP expression.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1178"}
{"PMID":25706130,"Year":2015,"Title":"MicroRNA markers for the diagnosis of pancreatic and biliary-tract cancers.","Abstract":"It is difficult to detect pancreatic cancer or biliary-tract cancer at an early stage using current diagnostic technology. Utilizing microRNA (miRNA) markers that are stably present in peripheral blood, we aimed to identify pancreatic and biliary-tract cancers in patients. With \"3D-Gene\", a highly sensitive microarray, we examined comprehensive miRNA expression profiles in 571 serum samples obtained from healthy patients, patients with pancreatic, biliary-tract, or other digestive cancers, and patients with non-malignant abnormalities in the pancreas or biliary tract. The samples were randomly divided into training and test cohorts, and candidate miRNA markers were independently evaluated. We found 81 miRNAs for pancreatic cancer and 66 miRNAs for biliary-tract cancer that showed statistically different expression compared with healthy controls. Among those markers, 55 miRNAs were common in both the pancreatic and biliary-tract cancer samples. The previously reported miR-125a-3p was one of the common markers; however, it was also expressed in other types of digestive-tract cancers, suggesting that it is not specific to cancer types. In order to discriminate the pancreato-biliary cancers from all other clinical conditions including the healthy controls, non-malignant abnormalities, and other types of cancers, we developed a diagnostic index using expression profiles of the 10 most significant miRNAs. A combination of eight miRNAs (miR-6075, miR-4294, miR-6880-5p, miR-6799-5p, miR-125a-3p, miR-4530, miR-6836-3p, and miR-4476) achieved a sensitivity, specificity, accuracy and AUC of 80.3%, 97.6%, 91.6% and 0.953, respectively. In contrast, CA19-9 and CEA gave sensitivities of 65.6% and 40.0%, specificities of 92.9% and 88.6%, and accuracies of 82.1% and 71.8%, respectively, in the same test cohort. This diagnostic index identified 18/21 operable pancreatic cancers and 38/48 operable biliary-tract cancers in the entire cohort. Our results suggest that the assessment of these miRNA markers is clinically valuable to identify patients with pancreato-biliary cancers who could benefit from surgical intervention.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-4294"}
{"PMID":25258651,"Year":2014,"Title":"Circulating microRNAs in Pancreatic Juice as Candidate Biomarkers of Pancreatic Cancer.","Abstract":"Development of sensitive and specific biomarkers, preferably those circulating in body fluids is critical for early diagnosis of cancer. This study performed profiling of microRNAs (miRNAs) in exocrine pancreatic secretions (pancreatic juice) by microarray analysis utilizing pancreatic juice from 6 pancreatic ductal adenocarcinoma (PDAC) patients and two pooled samples from 6 non-pancreatic, non-healthy (NPNH) as controls. Differentially circulating miRNAs were subsequently validated in 88 pancreatic juice samples from 50 PDAC, 19 chronic pancreatitis (CP) patients and 19 NPNH controls. A marked difference in the profiles of four circulating miRNAs (miR-205, miR-210, miR-492, and miR-1427) was observed in pancreatic juice collected from patients with PDAC and those without pancreatic disease. Elevated levels of the four miRNAs together predicted PDAC with a specificity of 88% and sensitivity of 87%. Inclusion of serum CA19-9 level increased the sensitivity to 91% and the specificity to 100%. Enrichment of the four miRNAs in pancreatic juice was associated with decreased OS, as was the combination of miR-205 and miR-210. Higher contents of miR-205 and miR-210 were also associated with lymph node metastasis. Elevated levels of circulating miR-205, miR-210, miR-492, and miR-1247 in pancreatic juice are, therefore, promising candidate biomarkers of disease and poor prognosis in patients with PDAC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1247"}
{"PMID":28529605,"Year":2017,"Title":"Mutual Regulation of MiR-199a-5p and HIF-1alpha Modulates the Warburg Effect in Hepatocellular Carcinoma.","Abstract":"The Warburg effect is one of the major metabolic changes of cancer cells, which characterized by high level of glycolysis even in the presence of oxygen. However, the role of microRNAs (miRNAs) in regulating the glycolytic switch in cancer cells has not been well explored. In this study, we demonstrated that miR-199a-5p acts as a suppressor of the Warburg effect in hepatocellular carcinoma (HCC). MiR-199a-5p directly targets the 3'-untranslated region (UTR) of hypoxia-inducible factor-1alpha (HIF-1alpha), thereby suppressing glucose uptake, lactate production, cell growth, and expression of HIF-1alpha downstream glycolytic genes of HCC cells. Moreover, under hypoxic conditions, the expression of miR-199a-5p is suppressed by the up-regulation of HIF-1alpha. Thus, mutual regulation between miR-199a-5p and HIF-1alpha forms a positive feedback loop to promote glycolysis in HCC cells. Furthermore, miR-199a-5p is down-regulated in human HCC tissues and its low-level expression is associated with a worse survival of patients with HCC. Our findings suggest that miR-199a-5p/HIF-1alpha axis is critical in the regulation of the Warburg effect and also implicate miR-199a-5p as a potential therapeutic target for HCC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-199"}
{"PMID":25030590,"Year":2014,"Title":"[Expression and clinical significance of plasma small RNA in patients with pancreatic cancer].","Abstract":"OBJECTIVE: The aim of this study was to identify six miRNAs expressed in plasma of patients with pancreatic cancer (PCa) and analyze their value as a diagnostic index of pancreatic cancer. METHODS: Plasma total RNAs were extracted from 30 PCa patients and 26 normal controls, and the abundance of six microRNAs was measured using real-time PCR. The possibility to combine them with CA19-9 as diagnostic biomarkers was analyzed. RESULTS: The expression level of miR-21, miR-210, miR-155, miR-20a, miR-25 and miR-196a in plasma of patients with pancreatic cancer were 1.65x10(6), 5.98x10(4), 2.83x10(3), 3.47x10(6), 2.76x10(6), and 1.03x10(3) (copies/microl), while the normal controls were 4.08x10(5), 2.54x10(4), 8.55x10(2), 1.79x10(6), 9.32x10(5), and 4.67x10(2) (copies/microl), respectively, with a significant difference between the two groups (P < 0.05). The areas under the ROC curve of miR-21, miR-210, miR-155, miR-20a, miR-25 and miR-196a were 0.893, 0.810, 0.820, 0.766, 0.816 and 0.729, respectively. MiR-21 had the highest diagnostic value when it was used as diagnostic marker alone. The combination of miR-155 and miR-25 was more effective to distinguish PCa from normal than to be used alone, and the area under the ROC curve was 0.913 (95%CI 0.838-0.988) .When CA199 associated with miR -210 and miR-25, respectively, the areas under the ROC curves were 0.96 (95%CI was 0-1.0) and 0.942 (95% CI was 0.876-1.0), which were higher than CA199 alone (0.862, 95%CI was 0.748-0.975). There was a high improvement in diagnostic sensitivity and accuracy when miR-210 and miR-25 were combined with CA19-9, respectively. CONCLUSIONS: Plasma miR-21, miR-155, miR-25, miR-210 have diagnostic value for pancreatic cancer, and deserve further study.","Language":"chi","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-210"}
{"PMID":21823013,"Year":2011,"Title":"Inhibitory effects of miR-146b-5p on cell migration and invasion of pancreatic cancer by targeting MMP16.","Abstract":"Previous studies have shown that miRNAs participate in a wide range of biological functions and play important roles in various human diseases including cancer. We found miR-146b-5p significantly dysregulated in human pancreatic cancer cells by qRT-PCR. To demonstrate its function and regulation mechanism, we overexpressed miR-146-5p by transfecting the mimics. Our data showed that miR-146b-5p overexpression significantly reduced the abilities of migration and invasion of MIA PaCa-2 pancreatic cancer cells. Furthermore, we found that matrix metalloproteinase 16 (MMP16) was a downstream target of miR-146b-5p by dual-luciferase reporter assay. Altogether, our findings suggest that miR-146b-5p may be involved in pancreatic cancer cell migration and invasion by targeting MMP16, and miR-146b-5p may be a potential therapeutic target for the pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-146"}
{"PMID":31510100,"Year":2019,"Title":"Differentially Expressed microRNAs in MIA PaCa-2 and PANC-1 Pancreas Ductal Adenocarcinoma Cell Lines are Involved in Cancer Stem Cell Regulation.","Abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and thus better understanding of its molecular pathology is crucial for us to devise more effective treatment of this deadly disease. As cancer cell line remains a convenient starting point for discovery and proof-of-concept studies, here we report the miRNA expression characteristics of two cell lines, MIA PaCa-2 and PANC-1, and discovered three miRNAs (miR-7-5p, let-7d, and miR-135b-5p) that are involved in cancer stem cells (CSCs) suppression. After transfection of each miRNA's mimic into PANC-1 cells which exhibits higher stemness feature than MIA-PaCa-2 cells, partial reduction of CSC surface markers and inhibition of tumor sphere formation were observed. These results enlighten us to consider miRNAs as potential therapeutic agents for pancreatic cancer patients via specific and effective inhibition of CSCs.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-7"}
{"PMID":28239461,"Year":2017,"Title":"Tissue MicroRNA profiles as diagnostic and prognostic biomarkers in patients with resectable pancreatic ductal adenocarcinoma and periampullary cancers.","Abstract":"BACKGROUND: The aim of this study was to validate previously described diagnostic and prognostic microRNA expression profiles in tissue samples from patients with pancreatic cancer and other periampullary cancers. METHODS: Expression of 46 selected microRNAs was studied in formalin-fixed paraffin-embedded tissue from patients with resected pancreatic ductal adenocarcinoma (n = 165), ampullary cancer (n=59), duodenal cancer (n = 6), distal common bile duct cancer (n = 21), and gastric cancer (n = 20); chronic pancreatitis (n = 39); and normal pancreas (n = 35). The microRNAs were analyzed by PCR using the Fluidigm platform. RESULTS: Twenty-two microRNAs were significantly differently expressed in patients with pancreatic cancer when compared to healthy controls and chronic pancreatitis patients; 17 miRNAs were upregulated (miR-21-5p, -23a-3p, -31-5p, -34c-5p, -93-3p, -135b-3p, -155-5p, -186-5p, -196b-5p, -203, -205-5p, -210, -222-3p, -451, -492, -614, and miR-622) and 5 were downregulated (miR-122-5p, -130b-3p, -216b, -217, and miR-375). MicroRNAs were grouped into diagnostic indices of varying complexity. Ten microRNAs associated with prognosis were identified (let-7 g, miR-29a-5p, -34a-5p, -125a-3p, -146a-5p, -187, -205-5p, -212-3p, -222-5p, and miR-450b-5p). Prognostic indices based on differences in expression of 2 different microRNAs were constructed for pancreatic and ampullary cancer combined and separately (30, 5, and 21 indices). CONCLUSION: The study confirms that pancreatic cancer tissue has a microRNA expression profile that is different from that of other periampullary cancers, chronic pancreatitis, and normal pancreas. We identified prognostic microRNAs and microRNA indices that were associated with shorter overall survival in patients with radically resected pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-187"}
{"PMID":26719072,"Year":2016,"Title":"miR-203 promotes proliferation, migration and invasion by degrading SIK1 in pancreatic cancer.","Abstract":"Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers and it is insensitive to many chemotherapeutic drugs. The molecular basis of pancreatic cancer remains to be elucidated. Investigations into the molecular mechanism involved in the development and progression as well as drug resistance of the disease may be useful to understand the pathogenesis and progression of the disease and offer new targets for effective therapies. In the present study, we showed that salt-inducible kinase 1 (SIK1) was downregulated and loss of SIK1 was associated with gemcitabine resistance in pancreatic cancer. In pancreatic cancer cells, SIK1 inhibited proliferation, migration and invasion. An analysis of potential microRNA target sites was performed using the prediction algorithms, miRanda, TargetScan and PicTar. The three algorithms predicted that miR-203 is capable of targeting 3'UTR of SIK1. Subsequent experiments confirmed the prediction. In addition, the results showed that miR-203 promotes proliferation, migration and invasion in pancreatic cancer cells, whereas the restoration of SIK1 abrogated the regulation of pre-miR203-mediated proliferation, migration and invasion.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-203"}
{"PMID":30483731,"Year":2019,"Title":"Potential fourmiRNA signature associated with T stage and prognosis of patients with pancreatic ductal adenocarcinoma identified by coexpression analysis.","Abstract":"With a 5year survival rate of only 8%, pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancerassociated mortality worldwide. Unfortunately, even following radical surgery, patient outcomes remain poor. Emerging as a new class of biomarkers in human cancer, microRNAs (miRNAs/miRs) have been reported to have various tumor suppressor and oncogenic functions. In the present study, miRNA expression profiles of patients with PDAC and corresponding clinical data with survival profiles were obtained from The Cancer Genome Atlas database. A coexpression network was constructed to detect the modules significantly associated with clinical features by weighted gene coexpression network analysis. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed on the hub miRNAs in the module of interest for functional annotation. A prognosis model consisting of hub miRNAs was generated using the R package 'rbsurv' and validated in survival analysis. The expression data of 523 miRNAs in 124 patients with PDAC were analyzed in a coexpression network. The turquoise module containing 131 miRNAs was identified to be associated with pathological T stage (cor=0.21; P=0.02). The 39 hub miRNAs of the turquoise module were then detected using the 'networkScreening' function in R. These miRNAs were predominantly involved in biological processes including 'regulation of transcription', 'apoptotic process', 'TGFbeta receptor signaling pathway', 'Ras protein signal transduction' and significantly enriched in 'cell cycle', 'adherens junction', 'FoxO', 'Hippo' and 'PI3KAkt signaling' pathways. A prognostic signature consisting of four hub miRNAs (miR1197, miR2182, miR889 and miR487a) associated with pathological T stage was identified to stratify the patients with earlystage PDAC into high and low risk groups. The signature may serve as a potential prognostic biomarker for patients with earlystage PDAC who undergo radical resection.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-1197"}
{"PMID":24732804,"Year":2014,"Title":"Mechanism of action of phenethylisothiocyanate and other reactive oxygen species-inducing anticancer agents.","Abstract":"Reactive oxygen species (ROS)-inducing anticancer agents such as phenethylisothiocyanate (PEITC) activate stress pathways for killing cancer cells. Here we demonstrate that PEITC-induced ROS decreased expression of microRNA 27a (miR-27a)/miR-20a:miR-17-5p and induced miR-regulated ZBTB10/ZBTB4 and ZBTB34 transcriptional repressors, which, in turn, downregulate specificity protein (Sp) transcription factors (TFs) Sp1, Sp3, and Sp4 in pancreatic cancer cells. Decreased expression of miR-27a/miR-20a:miR-17-5p by PEITC-induced ROS is a key step in triggering the miR-ZBTB Sp cascade leading to downregulation of Sp TFs, and this is due to ROS-dependent epigenetic effects associated with genome-wide shifts in repressor complexes, resulting in decreased expression of Myc and the Myc-regulated miRs. Knockdown of Sp1 alone by RNA interference also induced apoptosis and decreased pancreatic cancer cell growth and invasion, indicating that downregulation of Sp transcription factors is an important common mechanism of action for PEITC and other ROS-inducing anticancer agents.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-27"}
{"PMID":24096486,"Year":2014,"Title":"microRNA-10b enhances pancreatic cancer cell invasion by suppressing TIP30 expression and promoting EGF and TGF-beta actions.","Abstract":"Increased microRNA-10b (miR-10b) expression in the cancer cells in pancreatic ductal adenocarcinoma (PDAC) is a marker of disease aggressiveness. In the present study, we determined that plasma miR-10b levels are significantly increased in PDAC patients by comparison with normal controls. By gene profiling, we identified potential targets downregulated by miR-10b, including Tat-interacting protein 30 (TIP30). Immunoblotting and luciferase reporter assays confirmed that TIP30 was a direct miR-10b target. Downregulation of TIP30 by miR-10b or siRNA-mediated silencing of TIP30 enhanced epidermal growth factor (EGF)-dependent invasion. The actions of miR-10b were abrogated by expressing a modified TIP30 cDNA resistant to miR-10b. EGF-induced EGF receptor (EGFR) tyrosine phosphorylation and extracellular signal-regulated kinase phosphorylation were enhanced by miR-10b, and these effects were mimicked by TIP30 silencing. The actions of EGF in the presence of miR-10b were blocked by EGFR kinase inhibition with erlotinib and by dual inhibition of PI3K (phosphatidylinositol 3'-kinase) and MEK. Moreover, miR-10b, EGF and transforming growth factor-beta (TGF-beta) combined to markedly increase cell invasion, and this effect was blocked by the combination of erlotinib and SB505124, a type I TGF-beta receptor inhibitor. miR-10b also enhanced the stimulatory effects of EGF and TGF-beta on cell migration and epithelial-mesenchymal transition (EMT) and decreased the expression of RAP2A, EPHB2, KLF4 and NF1. Moreover, miR-10b overexpression accelerated pancreatic cancer cell (PCC) proliferation and tumor growth in an orthotopic model. Thus, plasma miR-10b levels may serve as a diagnostic marker in PDAC, whereas intra-tumoral miR-10b promotes PCC proliferation and invasion by suppressing TIP30, which enhances EGFR signaling, facilitates EGF-TGF-beta cross-talk and enhances the expression of EMT-promoting genes, whereas decreasing the expression of several metastasis-suppressing genes. Therefore, therapeutic targeting of miR-10b in PDAC may interrupt growth-promoting deleterious EGF-TGF-beta interactions and antagonize the metastatic process at various levels.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-10"}
{"PMID":28383557,"Year":2017,"Title":"Silencing NKG2D ligand-targeting miRNAs enhances natural killer cell-mediated cytotoxicity in breast cancer.","Abstract":"NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DLs). NKG2DLs are expressed on malignant cells and sensitize them to early elimination by cytotoxic lymphocytes. We investigated the clinical importance of NKG2DLs and the mechanism of NKG2DL regulation in breast cancer (BC). Among the NKG2DLs MICA/B and ULBP1/2/3, the expression levels of MICA/B in BC tissues were inversely associated with the Tumor Node Metastasis stage. We first found that the high expression of MICB, but not MICA, was an independent prognostic factor for overall survival in patients with BC. Investigation into the mechanism revealed that a group of microRNAs (miRNAs) belonging to the miR-17-92 cluster, especially miR-20a, decreased the expression of ULBP2 and MICA/B. These miRNAs downregulated the expression of MICA/B by targeting the MICA/B 3'-untranslated region and downregulated ULBP2 by inhibiting the MAPK/ERK signaling pathway. Functional analysis showed that the silencing of NKG2DL-targeting miRNAs in BC cells increased NK cell-mediated cytotoxicity in vitro and inhibited immune escape in vivo. In addition, histone deacetylase inhibitors (HDACis) increased NKG2DL expression in BC cells by inhibiting members of the miR-17-92 cluster. Thus, targeting miRNAs with antisense inhibitors or HDACis may represent a novel approach for increasing the immunogenicity of BC.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-17"}
{"PMID":30570107,"Year":2019,"Title":"Potential ceRNA networks involved in autophagy suppression of pancreatic cancer caused by chloroquine diphosphate: A study based on differentiallyexpressed circRNAs, lncRNAs, miRNAs and mRNAs.","Abstract":"Autophagy has been reported to be involved in the occurrence and development of pancreatic cancer. However, the mechanism of autophagyassociated noncoding RNAs (ncRNAs) in pancreatic cancer remains largely unknown. In the present study, microarrays were used to detect differential expression of mRNAs, microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs) post autophagy suppression by chloroquine diphosphate in PANC1 cells. Collectively, 3,966 mRNAs, 3,184 lncRNAs and 9,420 circRNAs were differentially expressed. Additionally, only two miRNAs (hsamiR663a5p and hsamiR1543p) were underexpressed in the PANC1 cells in the autophagysuppression group. Furthermore, miR663a5p with 9 circRNAs, 8 lncRNAs and 46 genes could form a prospective ceRNA network associated with autophagy in pancreatic cancer cells. In addition, another ceRNA network containing miR1543p, 5 circRNAs, 2 lncRNAs and 11 genes was also constructed. The potential multiple ceRNA, miRNA and mRNA associations may serve pivotal roles in the autophagy of pancreatic cancer cells, which lays the theoretical foundation for subsequent investigations on pancreatic cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-154"}
{"PMID":21225432,"Year":2011,"Title":"Frequent concomitant inactivation of miR-34a and miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas.","Abstract":"The microRNA encoding genes miR-34a and miR-34b/c represent direct p53 target genes and possess tumor suppressive properties as they mediate apoptosis, cell cycle arrest, and senescence. We previously reported that the miR-34a gene is subject to epigenetic inactivation by CpG methylation of its promoter region in primary prostate cancer and melanomas, and in 110 different cancer cell lines of diverse origin. Here we analyzed the methylation status of miR-34a and miR-34b/c in additional primary tumors of divergent sites. We found methylation of miR-34a or miR-34b/c in formalin-fixed, paraffin-embedded (FFPE) tumor samples from 178 patients with the following frequencies: colorectal cancer (74% miR-34a, 99% miR-34b/c; n = 114), pancreatic cancer (64%, 100%; n = 11), mammary cancer (60%, 90%; n = 10), ovarian cancer (62%, 69%; n = 13), urothelial cancer (71%, 57%; n = 7), and renal cell cancer (58%, 100%; n = 12). Furthermore, soft tissue sarcomas showed methylation of miR-34 gene promoters in FFPE samples (64%, 45%; n = 11), in explanted, cultured cells (53%, 40%; n = 40), and in frozen tissue samples (75%, 75%, n = 8). In the colorectal cancer samples a statistically significant correlation of miR-34a methylation and the absence of p53 mutation was detected. With the exception of sarcoma cell lines, the inactivation of miR-34a and miR-34b/c was concomitant in most cases. These results show that miR-34 inactivation is a common event in tumor formation, and suggest that CpG methylation of miR-34a and miR-34-b/c may have diagnostic value. The mutual exclusiveness of miR-34a methylation and p53 mutation indicates that miR-34a inactivation may substitute for loss of p53 function in cancer.","Language":"eng","Type":"Journal Article","Topic":"Pancreas","miRNA":"miR-34"}