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Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies
  1. Hsiao-Ping Chen1,2,
  2. Jeng-Jer Shieh3,4,
  3. Chia-Che Chang3,5,
  4. Tzu-Ting Chen4,
  5. Jaw-Town Lin2,6,7,
  6. Ming-Shiang Wu2,
  7. Jeng-Horng Lin1,
  8. Chun-Ying Wu4,5,8
  1. 1Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
  2. 2Division of Gastroenterology, National Taiwan University Hospital, Taipei, Taiwan
  3. 3Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
  4. 4Department of Education and Research and Division of Gastroenterology, Taichung Veterans General Hospital, Taichung, Taiwan
  5. 5Graduate Institute of Basic Medical Science and Department of Public Health, China Medical University, Taichung, Taiwan
  6. 6Department of Internal Medicine, E-Da Hospital and I-Shou University, Kaohsiung, Taiwan
  7. 7Center for Health Policy Research and Development, National Health Research Institutes; Miaoli, Taiwan
  8. 8Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
  1. Correspondence to Professor Chun-Ying Wu, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, 155, Sec. 2, Linong Street, Taipei 112, Taiwan; chun{at}vghtc.gov.tw

Abstract

Objective Type 2 diabetes mellitus is associated with a higher risk of hepatocellular carcinoma (HCC), which is attenuated by the use of metformin. However, there are no studies addressing the effect of metformin on hepatocarcinoma cells from the antitumoural perspective.

Design In the nationwide case-control study, the authors recruited 97 430 HCC patients and 194 860 age-, gender- and physician visit date-matched controls. The chemopreventive effects of metformin were examined by multivariate analysis and stratified analysis. The in vitro effects of metformin on cell proliferation and cell cycle were studied in HepG2 and Hep3B hepatoma cell lines.

Results The OR of diabetes in HCC patients was 2.29 (95% CI 2.25 to 2.35, p<0.001). Each incremental year increase in metformin use resulted in 7% reduction in the risk of HCC in diabetic patients (adjusted OR=0.93, 95% CI 0.91 to 0.94, p<0.0001). In the multivariate stratified analysis, metformin use was associated with a reduced risk of HCC in diabetic patients in nearly all subgroups. Cell line studies showed that metformin inhibits hepatocyte proliferation and induces cell cycle arrest at G0/G1 phase via AMP-activated protein kinase and its upstream kinase LKB1 to upregulate p21/Cip1 and p27/Kip1 and downregulate cyclin D1 in a dose-dependent manner, but independent of p53. Combined treatment of oral metformin with doxorubicin functioned more efficiently than either agent alone, in vivo.

Conclusions Use of metformin is associated with a decreased risk of HCC in diabetic patients in a dose-dependent manner, via inhibition of hepatoma cells proliferation and induction of cell cycle arrest at G0/G1 phase.

  • Hepatocellular carcinoma
  • diabetes
  • metformin
  • cell cycle
  • dose-dependent
  • Helicobacter pylori
  • molecular biology
  • cell biology
  • gastric lymphoma
  • gastric cancer
  • Helicobacter pylori–pathogenesis
  • molecular oncology
  • gastrointestinal neoplasia
  • gene expression
  • oxidative stress
  • cancer epidemiology
  • bleeding
  • aspirin

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Footnotes

  • Strobe guideline regarding bias and missing data has been followed.

  • Funding This work was supported in part by the Taiwan National Health Research Institutes (Grant number: PH-100-PP54, PH-101-PP-23) and Taichung Veterans General Hospital (Grand number: TCVGH-1013305C). The Taiwan National Health Research Institute provided the NHIRD and financial support for hiring research assistants.

  • Competing interests None.

  • Ethics approval Study approval: The present study used secondary database and cell lines, not involving human subjects. However, it was approved by the Taiwan National Health Research Institute.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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