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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

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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

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Project description:Purpose:STARD13 is regulated by various miRNAs. However, there are relatively few reports describing the relationship between miRNAs and STARD13 in pancreatic cancer. Therefore, the aim of this study was to explore the relationship between miRNA and STARD13 in pancreatic cancer. Patients and Methods:By analyzing the data from Gene Expression Omnibus (GEO) database, the relationship between STARD13 expression and pancreatic cancer was explored. Then, through sequence alignment, the sequence complementary to miR-887-3p in the 3'UTR of STARD13 mRNA was found, mutated and cloned. Dual-luciferase reporter assay was used to test the relationship between STARD13 and miR-887-3p. Pancreatic cancer tumor tissue and its adjacent tissues collected, and the expression of STARD13 and miR-887-3p in pancreatic cancer tissues was analyzed by RT-qPCR. After, miR-887-3p and its inhibitor were transfected into PANC-1 cells to further confirm the regulatory relationship between miR-887-3 and STARD13 by RT-qPCR, and CCK-8, colony formation assays, cell cycle analysis, apoptosis detection and transwell analysis were used to detect changes of proliferation, apoptosis, migration and invasion in PANC-1 cells. Finally, through in vivo experiments, the effect of miR-887-3p on tumor growth was researched. Results:We found that STARD13 expression is lower in pancreatic cancer tissues, with the level of miR-887-3p being higher in these tissues. Pancreatic cancer patients with particularly low levels of STARD13 presented with a poor prognosis. MiR-887-3p negatively regulates the expression of STARD13. Increasing levels of miR-887-3p decreased the expression of STARD13, which promoted the proliferation, cell cycle process, cell migration and invasion, and inhibited the apoptosis of pancreatic cancer cells. Inhibition of miR-887-3p in SCID mice could inhibit tumor growth and promote tumor cell apoptosis. Conclusion:In conclusion, STARD13 is negatively regulated by miR-887-3p in pancreatic cancer. MiR-877-3p may act to promote cancer progression, and as such, it is a viable target for intervention and diagnostic development.

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.

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