title: Metformin inhibits tumor growth by regulating multiple miRNAs in human cholangiocarcinoma.
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.
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Xingming
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Ma
authors.affiliation: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors.forename: Dayong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Center for Endemic Disease Control, Harbin Medical University, Harbin, China.
authors.forename: Fuyuan
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors.forename: Rongzhang
authors.initials: R
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors.forename: Dongliang
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors.forename: Ruiqi
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Qingxin
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Fumin
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Wan
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Yunfu
authors.initials: Y
authors.lastname: Cui
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000601:surgery*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000601:surgery*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008687:Metformin / Q000627:therapeutic use*; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007004:Hypoglycemic Agents; D035683:MicroRNAs; D008687:Metformin; C517918:DROSHA protein, human; D043244:Ribonuclease III