Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-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-β2 (TGF-β2), as top candidates. miR-132 mimics directly bound to the 3′ untranslated region (3′UTR) of a TGF-β2 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-β2 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.

A novel mRNA-miRNA-lncRNA competing endogenous RNA triple sub-network associated with prognosis of pancreatic cancer

“…For example, Abukiwan et al . suggested that inhibition of miR-132-3p drove progression of pancreatic cancer [39]; miR-133a-5p was also found to function as a tumor suppressor in pancreatic cancer [40,41]; the group of Wang Lihua showed that miR-29b-3p decreased proliferation and mobility of pancreatic cancer by targeting SOX12 and DNMT3b [42]. Then, we further predicted 90 upstream lncRNAs of these key miRNAs.…”

Glucocorticoid receptor antagonism promotes apoptosis in solid tumor cells

“…GR activity may underly the switch into the drug tolerant state by modifying the biological processes implicated in DTP emergence. GR activity has been demonstrated to affect such processes, including transcriptional reprograming, epigenetics, epithelial to mesenchymal transition, and TGFβ activity [23,[27][28][29] . Proposed DTP targets KDM5A and GPX4 [3,30] are like GR in their heterogeneous and reversible involvement in these processes.…”

MicroRNAs as systemic biomarkers to assess distress in animal models for gastrointestinal diseases

“…This suggests that miR-132 expression is not induced by a pancreatogenic diabetes mellitus secondary to chronic pancreatitis. The connection of miR-132 expression and pancreatic cancer is controversially discussed in the literature, some studies reported a downregulation of the miR-132 expression in cancer tissue and cells 60 – 62 , while other studies confirmed an upregulation of miR-132 63 – 65 . The hepatic expression of miR-132 is reported to be upregulated after alcoholic hepatitis 66 , nonalcoholic fatty liver disease (NAFLD), hepatic steatosis 67 , as well as cholestasis 68 .…”