miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1 (original) (raw)
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Cancer Biology & Therapy, 2009
MicroRNAs (miRNAs) are 21-24 nucleotide RNA molecules that regulate the translation and stability of target messenger RNAs. Abnormal miRNA expression is a common feature of diverse cancers. Several previous studies have classified miRNA expression in pancreatic ductal adenocarcinoma (PDAC), although no uniform pattern of miRNA dysregulation has emerged. To clarify these previous findings as well as to set the stage for detailed functional analyses, we performed global miRNA expression profiling of 21 human PDAC cell lines, the most extensive panel studied to date. Overall, 39 miRNAs were found to be dysregulated and have at least two-fold or greater differential expression in PDAC cell lines compared to control non-transformed pancreatic ductal cell lines. Several of these miRNAs show comparable dysregulation in first-passage patientderived xenografts. Initial functional analyses demonstrate that enforced expression of miRNAs derived from the miR-200 family and the miR-17-92 cluster, both of which are overexpressed in PDAC cell lines, enhances proliferation. In contrast, inhibition of the miR-200 family, the miR-17-92 cluster, or miR-191 diminishes anchorage independent growth. Consistent with a known role for the miR-200 family in negatively regulating an epithelial-to-mesenchymal transition (EMT), the abundance of these miRNAs correlated positively with E-cadherin expression and negatively with the EMT-associated transcription factor and established miR-200 target ZEB1. Finally, restituted expression of miR-34a, a miRNA whose expression is frequently lost in PDAC cell lines, abrogates growth, demonstrating that the anti-proliferative activity of this miRNA is operative in PDAC. These results, and the widespread availability of PDAC cell lines wherein the aforementioned data were generated, provide a valuable resource for the pancreatic cancer research community and will greatly facilitate functional studies essential for elucidating the consequences of miRNA dysregulation in pancreatic cancer.
Oncotarget, 2017
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.
International Journal of Molecular Sciences
Therapy for pancreatic ductal adenocarcinoma remains challenging, and the chances of a complete cure are very limited. As in other types of cancer, the expression and role of miRNAs in controlling the biological properties of this type of tumor have been extensively studied. A better insight into miRNA biology seems critical to refining diagnostics and improving their therapeutic potential. In this study, we focused on the expression of miR-21, -96, -196a, -210, and -217 in normal fibroblasts, cancer-associated fibroblasts prepared from a ductal adenocarcinoma of the pancreas, and pancreatic carcinoma cell lines. We compared these data with miRNAs in homogenates of paraffin-embedded sections from normal pancreatic tissues. In cancer-associated fibroblasts and cancer cell lines, miRNAs differed significantly from the normal tissue. In detail, miR-21 and -210 were significantly upregulated, while miR-217 was downregulated. Similar transcription profiles were earlier reported in cancer...
MicroRNA miR-155 is a biomarker of early pancreatic neoplasia
Cancer Biology & Therapy, 2009
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 pancreatobiliary 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.
MicroRNA Alterations of Pancreatic Intraepithelial Neoplasias
Clinical Cancer Research, 2011
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...
The miRacle in Pancreatic Cancer by miRNAs: Tiny Angels or Devils in Disease Progression
International Journal of Molecular Sciences, 2016
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with increasing incidence and high mortality. Surgical resection is the only potentially curative treatment of patients with PDAC. Because of the late presentation of the disease, about 20 percent of patients are candidates for this treatment. The average survival of resected patients is between 12 and 20 months, with a high probability of relapse. Standard chemo and radiation therapies do not offer significant improvement of the survival of these patients. Furthermore, novel treatment options aimed at targeting oncogenes or growth factors in pancreatic cancer have proved unsuccessful. Thereby, identifying new biomarkers that can detect early stages of this disease is of critical importance. Among these biomarkers, microRNAs (miRNAs) have supplied a profitable recourse and become an attractive focus of research in PDAC. MiRNAs regulate many genes involved in the development of PDAC through mRNA degradation or translation inhibition. The possibility of intervention in the molecular mechanisms of miRNAs regulation could begin a new generation of PDAC therapies. This review summarizes the reports describing miRNAs involvement in cellular processes involving pancreatic carcinogenesis and their utility in diagnosis, survival and therapeutic potential in pancreatic cancer.
The Rescue of miR-148a Expression in Pancreatic Cancer: An Inappropriate Therapeutic Tool
PLoS ONE, 2013
MicroRNAs are small non-coding RNAs that physiologically modulate proteins expression, and regulate numerous cellular mechanisms. Alteration of microRNA expression has been described in cancer and is associated to tumor initiation and progression. The microRNA 148a (miR-148a) is frequently down-regulated in cancer. We previously demonstrated that its down-regulation by DNA hypermethylation is an early event in pancreatic ductal adenocarcinoma (PDAC) carcinogenesis, suggesting a tumor suppressive function. Here, we investigate the potential role of miR-148a over-expression in PDAC as a therapeutic tool. We first report the consequences of miR-148a over-expression in PDAC cell lines. We demonstrate that miR-148a over-expression has no dramatic effect on cell proliferation and cell chemo-sensitivity in four well described PDAC cell lines. We also investigate the modulation of protein expression by a global proteomic approach (2D-DIGE). We show that despite its massive over-expression, miR-148a weakly modulates protein expression, thus preventing the identification of protein targets in PDAC cell lines. More importantly, in vivo data demonstrate that modulating miR-148a expression either in the epithelia tumor cells and/or in the tumor microenvironment does not impede tumor growth. Taken together, we demonstrate herein that miR-148a does not impact PDAC proliferation both in vitro and in vivo thus suggesting a weak potential as a therapeutic tool.
Laboratory Investigation, 2011
MicroRNAs (miRNAs: short non-coding RNAs) are emerging as a class of potential novel tumor markers, as their dysregulation is being increasingly reported in various types of cancers. In the present study, we investigated the transcription status of miRNA-148a (miR-148a) in human pancreatic ductal adenocarcinoma (PDAC) and its role in the regulation of the dual specificity protein phosphatase CDC25B. We observed that miR-148a exhibited a significant 4-fold down-regulation in PDAC as opposed to normal pancreatic ductal cells. In addition, we observed that stable lentiviral-mediated overexpression of miR-148a in the pancreatic cancer cell line IMIM-PC2, inhibited tumor cell growth and colony formation. Furthermore, CDC25B was identified as a potential target of miR-148a by in silico analysis using PicTar, Targetscan and miRanda in conjunction with gene ontology analysis. The proposed interaction between miR-148a and the 3 0 untranslated region (UTR) of CDC25B was verified by in-vitro luciferase assays. We demonstrate that the activity of a luciferase reporter containing the 3 0 UTR of CDC25B was repressed in the presence of miR-148a mimics, confirming that miR-148a targets the 3 0 UTR of CDC25B. Finally, CDC25B was down-regulated at the protein level in miR-148a overexpressing IMIM-PC2-cells, and in transiently transfected pancreatic cell lines (as detected by Western blot analysis), as well as in patient tumor samples (as detected by immunohistochemistry). In summary, we identified CDC25B as a novel miR-148a target which may confer a proliferative advantage in PDAC.
microRNAs as markers of survival and chemoresistance in pancreatic ductal adenocarcinoma
Expert Review of Anticancer Therapy, 2011
Methods microRNAs (miRs) shown by previous studies to be overexpressed in pancreatic ductal adenocarcinoma (PDAC) compared with normal tissue were evaluated (miR-21, miR-10b, miR-155, miR-196a and miR-210). Previously, only Bloomston et al. demonstrated miR-10b to be upregulated in PDAC [1]. The authors suggest this is due to contamination in other studies from proliferating stromal cells in the extensive desmoplasia around PDAC lesions, as well as endocrine islets and acinar cells present in the tumor mass [2], leading to an inaccurate representation of deregulated miRs. To resolve this, the spatial expression of selected miRs was quantified via a novel system of fluorescence-based in situ hybridization (ISH)using locked nucleic acid (LNA)-modified DNA probes against various miRs, followed by codetection of proteins (cytokeratin 19 and amylase) by immunohistochemistry (IHC) on the same formalin-fixed paraffin embedded sections. miR expression (normalized to U6 snRNA) was therefore only assessed in cytokeratin 19 (CK19)-positive epithelial cells (i.e., true ductal cells) using optical intensity analysis. Normal pancreas was confirmed by an abundance of amylase-positive acinar cells and few CK19-positive cells. By this method, miR-10b expression was examined in postsurgical specimens (PDAC: n = 10; noncancerous: n = 3; eight normal adjacent tissue samples were available) and endoscopic-ultrasound guided fine-needle aspiration (EUS-FNA) samples from patients under investigation for suspicious pancreatic lesions (confirmed PDAC: n = 95; benign: n = 11). FNA samples were fixed in 10% formalin or ethanol, embedded in paraffin, cut into 4 µm sections and mounted on positively-charged barrier frame slides prior to ISH/IHC assay. miR-10b expression was correlated with standard clinicopathological features and