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Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 21, 2016; 22(27): 6100-6113
Published online Jul 21, 2016. doi: 10.3748/wjg.v22.i27.6100
Diabetes mellitus and metformin in hepatocellular carcinoma
Koji Fujita, Hisakazu Iwama, Hisaaki Miyoshi, Joji Tani, Kyoko Oura, Tomoko Tadokoro, Teppei Sakamoto, Takako Nomura, Asahiro Morishita, Hirohito Yoneyama, Tsutomu Masaki
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
Hisakazu Iwama, Life Science Research Center, Kagawa University, Kagawa 760-8521, Japan
Author contributions: All authors made contributions to this manuscript.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Tsutomu Masaki, Professor, Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Ikenobe 1750-1, Miki, Kita, Kagawa 760-8521, Japan. tmasaki@med.kagawa-u.ac.jp
Telephone: +81-87-8912156 Fax: +81-87-8912158
Received: March 28, 2016
Peer-review started: March 29, 2016
First decision: May 12, 2016
Revised: May 25, 2016
Accepted: June 15, 2016
Article in press: June 15, 2016
Published online: July 21, 2016
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.

Keywords: Hepatocellular carcinoma, Diabetes mellitus, Metformin, Risk

Core tip: Diabetes mellitus, an increasing risk factor for hepatocellular carcinoma (HCC), shares pathological mechanisms with HCC. Thus, the first-line anti-diabetic metformin was anticipated to reduce cancer risk. Though basic research has provided evidence of its anti-cancer effect, clinical studies of diabetic patients have not provided conclusive data that metformin reduces HCC risk. Clinical studies have suggested that metformin may suppress cancer in non-diabetic subjects. Basic research on cancer stem cell-targeting therapies has also examined the potential of metformin.