Metformin inhibits tumor growth by regulating multiple miRNAs in human cholangiocarcinoma
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Xingming Jiang1, Ning Ma2, Dayong Wang2, Fuyuan Li3, Rongzhang He2, Dongliang Li2, Ruiqi Zhao2, Qingxin Zhou1, Yimin Wang1, Fumin Zhang1, Ming Wan1, Pengcheng Kang1, Xu Gao2 and Yunfu Cui1
1 Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
2 Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
3 Center for Endemic Disease Control, Harbin Medical University, Harbin, China
Yunfu Cui, email:
Xu Gao, email:
Keywords: metformin, cholangiocarcinoma, microRNA, cell cycle, prognosis
Received: October 08, 2014 Accepted: December 12, 2014 Published: December 18, 2014
The antidiabetic drug metformin exerts antineoplastic effects in many types of malignancies, however the effect of metformin on cholangiocarcinoma (CCA) still remains unclear. In the present study, we investigated that metformin treatment was closely associated with the clinicopathologic characteristics and improved postoperative survival of CCA patients. Metformin inhibited CCA tumor growth by cell cycle arrest in vitro and in vivo. We explored that the expression of six miRNAs (mir124, 182, 27b, let7b, 221 and 181a), which could directly target cell-cycle-regulatory genes, was altered by metformin in vitro and in vivo. These miRNAs were dysregulated in cholangiocarcinoma and promoted the CCA genesis and metformin exactly modulated these carcinogenic miRNAs expression to arrest the cell cycle and inhibit the proliferation. Meanwhile, these miRNAs expression changes correlated with the tumor volume and postoperative survival of CCA patients and could be used to predict the prognosis. Further we confirmed that metformin upregulated Drosha to modulate these miRNAs expression. Our results elucidated that metformin inhibited CCA tumor growth via the regulation of Drosha-mediated multiple carcinogenic miRNAs expression and comprehensive evaluation of these miRNAs expression could be more efficient to predict the prognosis. Moreover, metformin might be a quite promising strategy for CCA prevention and treatment.
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