title: Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo.
abstract: Metformin is a commonly used oral anti-hyperglycemic agent of the biguanide family. Recent studies suggest that metformin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of metformin in several types of cancers, including hepatocellular carcinoma (HCC), has not been elucidated. The goal of the present study was to evaluate the effects of metformin on HCC cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin in vitro. We used the cell lines Alex, HLE and Huh7, and normal hepatocytes to study the effects of metformin on human HCC cells. In an in vivo study, athymic nude mice bearing xenograft tumors were treated with metformin or left untreated. Tumor growth was recorded after 4 weeks, and the expression of cell cycle-related proteins was determined. Metformin inhibited the proliferation of Alex, HLE and Huh7 cells in vitro and in vivo. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, cyclin E and cyclin-dependent kinase 4 (Cdk4). In addition, microRNA (miRNA) expression was markedly altered by the treatment with metformin in vitro and in vivo. In addition, various miRNAs induced by metformin also may contribute to the suppression of tumor growth. Our results demonstrate that metformin inhibits the growth of HCC, possibly by inducing G1 cell cycle arrest through the alteration of microRNAs.
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Kato
authors.affiliation: Life Science Research Center, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Iwama
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Maeda
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Toyota
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Tani
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Nomura
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Shima
authors.initials: S
authors.lastname: Mimura
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Mitsuyoshi
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Asahiro
authors.initials: A
authors.lastname: Morishita
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Kobara
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yoneyama
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Deguchi
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Himoto
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Kurokohchi
authors.affiliation: Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Okano
authors.affiliation: Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Laboratory Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Murao
authors.affiliation: Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008114:Liver Neoplasms, Experimental; D008687:Metformin / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D008687:Metformin