title: Diabetes mellitus and metformin in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide. Diabetes mellitus, a risk factor for cancer, is also globally endemic. The clinical link between these two diseases has been the subject of investigation for a century, and diabetes mellitus has been established as a risk factor for HCC. Accordingly, metformin, a first-line oral anti-diabetic, was first proposed as a candidate anti-cancer agent in 2005 in a cohort study in Scotland. Several subsequent large cohort studies and randomized controlled trials have not demonstrated significant efficacy for metformin in suppressing HCC incidence and mortality in diabetic patients; however, two recent randomized controlled trials have reported positive data for the tumor-preventive potential of metformin in non-diabetic subjects. The search for biological links between cancer and diabetes has revealed intracellular pathways that are shared by cancer and diabetes. The signal transduction mechanisms by which metformin suppresses carcinogenesis in cell lines or xenograft tissues and improves chemoresistance in cancer stem cells have also been elucidated. This review addresses the clinical and biological links between HCC and diabetes mellitus and the anti-cancer activity of metformin in clinical studies and basic experiments.
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fujita
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Iwama
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Miyoshi
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Tani
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Oura
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tadokoro
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Nomura
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Asahiro
authors.initials: A
authors.lastname: Morishita
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Yoneyama
authors.affiliation: Koji Fujita, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa 760-8521, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000517:prevention & control*; D015897:Comorbidity; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000453:epidemiology / Q000517:prevention & control*; D008687:Metformin / Q000627:therapeutic use*; D012307:Risk Factors
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin
keywords: Diabetes mellitus; Hepatocellular carcinoma; Metformin; Risk