Metformin inhibits tumor growth by regulating multiple miRNAs in human cholangiocarcinoma

// Xingming Jiang 1 , Ning Ma 2 , Dayong Wang 2 , Fuyuan Li 3 , Rongzhang He 2 , Dongliang Li 2 , Ruiqi Zhao 2 , Qingxin Zhou 1 , Yimin Wang 1 , Fumin Zhang 1 , Ming Wan 1 , Pengcheng Kang 1 , Xu Gao 2 and Yunfu Cui 1 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 Correspondence: 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 Abstract 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.