Oncotarget

Research Papers:

MiR-199a-3p enhances cisplatin sensitivity of cholangiocarcinoma cells by inhibiting mTOR signaling pathway and expression of MDR1

Qiang Li, Xuefeng Xia, Jie Ji, Jianghui Ma, Liang Tao, Linjun Mo and Wei Chen _

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Oncotarget. 2017; 8:33621-33630. https://doi.org/10.18632/oncotarget.16834

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Abstract

Qiang Li1,*, Xuefeng Xia1,*, Jie Ji2, Jianghui Ma1, Liang Tao1, Linjun Mo3, Wei Chen4

1Department of General Surgery, The Afflicted Drum Tower Hospital of Nanjing University Medical School, Nanjing, China

2Nangjing Medical University, Nangjing, China

3School of Surgery, The University of Western Australia, and Western Australia Liver and Kidney Surgical Transplant Service, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia

4Institute of Molecular Engineering, University of Chicago, Chicago, Illinois, USA

*These authors contributed equally to this work and share the first authorship

Correspondence to:

Qiang Li, email: liqiang0912@126.com

Wei Chen, email: viogro@163.com

Keywords: MiR-199a-3p, cholangiocarcinoma, mTOR, MDR1, chemosensitivity

Received: December 14, 2016     Accepted: March 26, 2017     Published: April 04, 2017

ABSTRACT

Several studies have reported reduced miRNA-199a-3p (miR-199a-3p) in different human malignancies, however, little is known about miR-199a-3p in cholangiocarcinoma cells. In this study, we demonstrate the essential role and mechanism of miR-199a-3p in regulating cisplatin sensitivity in cholangiocarcinoma cell lines. Using a CCK-8 cell counting assay we found that expression of miR-199a-3p was positively correlated with cisplatin sensitivity in cholangiocarcinoma cell lines. MiR-199a-3p overexpression could decrease the proliferation rate and increase apoptosis of cholangiocarcinoma cells in the presence of cisplatin, while miR-199a-3p inhibition had the opposite effect. Further study demonstrated that mTOR was the target gene of miR-199a-3p, and that miR-199a-3p mimics could inhibit expression of mTOR, which consequently reduced the phosphorylation of its downstream proteins 4EBP1 and p70s6k. Rescue experiments proved that miR-199a-3p could increase the cisplatin sensitivity of cholangiocarcinoma cell lines by regulating mTOR expression. Moreover, we also found that miR-199a-3p overexpression could reduce cisplatin induced MDR1 expression by decreasing the synthesis and increasing the degradation of MDR1, thus enhancing the effectiveness of cisplatin in cholangiocarcinoma. In conclusion, miR-199a-3p could increase cisplatin sensitivity of cholangiocarcinoma cell lines by inhibiting the activity of the mTOR signaling pathway and decreasing the expression of MDR1.


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