Metformin Increases the Chemosensitivity of Pancreatic Cancer Cells to Gemcitabine by Reversing EMT Through Regulation DNA Methylation of miR-663
Authors Gu Y, Zhang B, Gu G, Yang X, Qian Z
Received 15 May 2020
Accepted for publication 6 September 2020
Published 14 October 2020 Volume 2020:13 Pages 10417—10429
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Jianmin Xu
Yuqing Gu, Bin Zhang, Guangliang Gu, Xiaojun Yang, Zhuyin Qian
Pancreas Center, The Second Affiliated Hospital to Nanjing Medical University, Nanjing 210003, People’s Republic of China
Correspondence: Zhuyin Qian Email firstname.lastname@example.org
Background: Pancreatic cancer is a devastating malignancy with poor prognosis. Metformin, a classic anti-diabetes drug, seems to improve survival of pancreatic cancer patients in some studies.
Methods: Cell counting kit-8 assay was used to detect the BxPC-3 and MIAPaCa-2 cell viability after treatment with gemcitabine only or with different concentrations of metformin. The methylation state and expression level of miR-663 were detected by methylation analysis and RT-PCR. Dual-luciferase reporter gene analysis, Western blot and RT-PCR were used to confirm the target of miR-663. Moreover, xenograft experiment was also performed to validate the role of metformin in chemosensitivity in vivo.
Results: We found that metformin increased the chemosensitivity of pancreatic cancer cells to gemcitabine, and epithelial–mesenchymal transition (EMT) progress caused by gemcitabine was suppressed by metformin. We further explored the possible molecular mechanisms and it was demonstrated that CpG islands of miR-663 were hypomethylated and relative expression level of miR-663 was up-regulated after treatment of metformin. miR-663, an important cancer suppressor miRNA, was confirmed to increase the chemosensitivity of pancreatic cancer cells by reversing EMT directly targeted TGF-β 1. Moreover, we identified that metformin increased the chemosensitivity through up-regulating expression of miR-663.
Conclusion: We demonstrated that metformin increased the chemosensitivity of pancreatic cancer cells to gemcitabine by reversing EMT through regulation DNA methylation of miR-663.
Keywords: metformin, pancreatic cancer, epithelial-mesenchymal transition; EMT, DNA methylation, miR-663
This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.Download Article [PDF] View Full Text [HTML][Machine readable]