Dataset Information

Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-?-driven progression of pancreatic cancer.

ABSTRACT: Glucocorticoids (GCs) such as dexamethasone (DEX) are administered as cancer co?treatment for palliative purposes due to their pro?apoptotic effects in lymphoid cancer and limited side effects associated with cancer growth and chemotherapy. However, there is emerging evidence that GCs induce therapy resistance in most epithelial tumors. Our recent data reveal that DEX promotes the progression of pancreatic ductal adenocarcinoma (PDA). In the present study, we examined 1 primary and 2 established PDA cell lines, and 35 PDA tissues from patients who had received (n=14) or not received (n=21) GCs prior to surgery. Through microRNA microarray analysis, in silico, and RT?qPCR analyses, we identified 268 microRNAs differentially expressed between DEX?treated and untreated cells. With a focus on cancer progression, we selected miR?132 and its target gene, transforming growth factor-?2 (TGF??2), as top candidates. miR?132 mimics directly bound to the 3' untranslated region (3'UTR) of a TGF??2 luciferase construct and enhanced expression, as shown by increased luciferase activity. By contrast, DEX inhibited miR?132 expression via promoter methylation. miR?132 mimics also reduced DEX?induced clonogenicity, migration and expression of vimentin and E?cadherin in vitro and in tumor xenografts. In patients, GC intake prior to surgery enhanced global hypermethylation and expression of TGF??2 in tissues; expression of miR?132 was detected but could not be quantified. Our results demonstrate that DEX?mediated inhibition of miR?132 is a key mediator in the progression of pancreatic cancer, and the findings provide a foundation for miRNA?based therapies.

SUBMITTER: Abukiwan A

PROVIDER: S-EPMC6255064 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer.

Abukiwan Alia A Nwaeburu Clifford C CC Bauer Nathalie N Zhao Zhefu Z Liu Li L Gladkich Jury J Gross Wolfgang W Benner Axel A Strobel Oliver O Fellenberg Jörg J Herr Ingrid I

International journal of oncology 20181101 1

Glucocorticoids (GCs) such as dexamethasone (DEX) are administered as cancer co‑treatment for palliative purposes due to their pro‑apoptotic effects in lymphoid cancer and limited side effects associated with cancer growth and chemotherapy. However, there is emerging evidence that GCs induce therapy resistance in most epithelial tumors. Our recent data reveal that DEX promotes the progression of pancreatic ductal adenocarcinoma (PDA). In the present study, we examined 1 primary and 2 established ...[more]

PMID: 30387838

Similar Datasets

Project description:ObjectiveMicroRNAs (miRNAs) play an integral role in maintaining beta cell function and identity. Deciphering their targets and precise role, however, remains challenging. In this study, we aimed to identify miRNAs and their downstream targets involved in the regeneration of islet beta cells following partial pancreatectomy in mice.MethodsRNA from laser capture microdissected (LCM) islets of partially pancreatectomized and sham-operated mice were profiled with microarrays to identify putative miRNAs implicated in beta cell regeneration. Altered expression of the selected miRNAs, including miR-132, was verified by RT-PCR. Potential targets of miR-132 were selected through bioinformatic data mining. Predicted miR-132 targets were validated for their changed RNA, protein expression levels, and signaling upon miR-132 knockdown and/or overexpression in mouse MIN6 and human EndoC-βH1 insulinoma cells. The ability of miR-132 to foster beta cell proliferation in vivo was further assessed in pancreatectomized miR-132-/- and control mice.ResultsPartial pancreatectomy significantly increased the number of BrdU+/insulin+ islet cells. Microarray profiling revealed that 14 miRNAs, including miR-132 and -141, were significantly upregulated in the LCM islets of the partially pancreatectomized mice compared to the LCM islets of the control mice. In the same comparison, miR-760 was the only downregulated miRNA. The changed expression of these miRNAs in the islets of the partially pancreatectomized mice was confirmed by RT-PCR only in the case of miR-132 and -141. Based on previous knowledge of its function, we focused our attention on miR-132. Downregulation of miR-132 reduced the proliferation of MIN6 cells while enhancing the levels of pro-apoptotic cleaved caspase-9. The opposite was observed in miR-132 overexpressing MIN6 cells. Microarray profiling, RT-PCR, and immunoblotting of the latter cells demonstrated their downregulated expression of Pten with concomitant increased levels of pro-proliferative factors phospho-Akt and phospho-Creb and inactivation of pro-apoptotic Foxo3a via its phosphorylation. Downregulation of Pten was further confirmed in the LCM islets of pancreatectomized mice compared to the sham-operated mice. Moreover, overexpression of miR-132 correlated with increased proliferation of EndoC-βH1 cells. The regeneration of beta cells following partial pancreatectomy was lower in the miR-132/212-/- mice than the control littermates.ConclusionsThis study provides compelling evidence about the critical role of miR-132 for the regeneration of mouse islet beta cells through the downregulation of its target Pten. Hence, the miR-132/Pten/Akt/Foxo3 signaling pathway may represent a suitable target to enhance beta cell mass.

Dataset Information

Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-?-driven progression of pancreatic cancer.

Publications

Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets