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.
Highlights
Cholangiocarcinoma (CCA), the second most common primary hepatobiliary malignancy, is a fatal cancer originating from the neoplastic transformation of biliary epithelial cells and characterized by increasing incidence worldwide and poor prognosis [1]
The results showed that metformin treatment was closely associated with a decrease in the tumor size and volume of CCA patients, and the improved postoperative survival
Log (Drosha expression change) 10 was defined as the cutoff value of Drosha expression change of G2 patients and High Drosha patients had smaller tumor volume and longer postoperative survival (Fig. 9D-E). These results indicated that dysregulated Drosha/DGCR8, which upstream regulated these carcinogenic miRNAs expression, promoted the CCA genesis and Drosha expression might be used to predict the prognosis for CCA patients
Summary
Cholangiocarcinoma (CCA), the second most common primary hepatobiliary malignancy, is a fatal cancer originating from the neoplastic transformation of biliary epithelial cells and characterized by increasing incidence worldwide and poor prognosis [1]. According to clinical statistical study, approximately 7500 new cases of cholangiocarcinoma are diagnosed per year in the United. Metformin is the most widely used antidiabetic drug in the world, introduced into clinical practice in the 1950s for the treatment of type II diabetes [6], and there is increasing evidence of the potential efficacy of this agent as an anticancer drug recently [7, 8]. It has been reported that patients with type II diabetes who are prescribed metformin have a lower risk of pancreatic www.impactjournals.com/oncotarget cancer than those not taking metformin [11]. Metformin has been recognized as an antidiabetic drug but a potentially preventive and therapeutic anticancer drug [9, 12, 13, 16]
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