title: Antitumor effect of metformin on cholangiocarcinoma: In vitro and in vivo studies.
abstract: Cholangiocarcinoma (CCA) is the most common biliary malignancy and the second most common hepatic malignancy after hepatocellular carcinoma (HCC). Treatment with the anti-diabetic drug metformin has been associated with reduced cancer incidence in patients with type 2 diabetes. Thus, the present study evaluated the effects of metformin on human CCA cell proliferation in vitro and in vivo and identified the microRNAs associated with its antitumor effects. Metformin inhibited the proliferation of the CCA cell lines HuCCT-1 and TFK-1 and blocked the G0 to G1 cell cycle transition, accompanied by AMP kinase pathway activation. Metformin treatment also led to marked decreases in cyclin D1 and cyclin-dependent kinase (Cdk) 4 protein levels and retinoblastoma protein phosphorylation. However, this drug did not affect p27kip protein expression. In addition, it reduced the phosphorylation of Axl, EphA10, ALK and PYK, as well as tumor proliferation in athymic nude mice with xenograft tumors. Furthermore, it markedly altered microRNA expression. These findings suggest that metformin may have clinical use in the treatment of CCA.
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujimori
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Fujihara
authors.affiliation: Life Science Research Center, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Iwama
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kamada
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Asahiro
authors.initials: A
authors.lastname: Morishita
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kobara
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Gastroenterological Surgery, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Okano
authors.affiliation: Department of Gastroenterological Surgery, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Gastroenterology and Neurology, Kagawa University, Faculty of Medicine, Graduate School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D018281:Cholangiocarcinoma / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008687:Metformin / Q000008:administration & dosage*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000187:drug effects*; D009363:Neoplasm Proteins / Q000096:biosynthesis; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; D009363:Neoplasm Proteins; D008687:Metformin