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Metformin prevents liver tumourigenesis by attenuating fibrosis in a transgenic mouse model of hepatocellular carcinoma

Oncogene volume 38, pages 7035–7045 (2019)Cite this article

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Abstract

Metformin is a hypoglycaemic agent used to treat type 2 diabetes mellitus (DM2) patients, with a broad safety profile. Since previous epidemiological studies had shown that the incidence of hepatocellular carcinoma (HCC) decreased significantly in metformin treated DM2 patients, we hypothesised that intervention with metformin could reduce the risk of neoplastic transformation of hepatocytes. HCC is the most common primary liver malignancy and it generally originates in a background of liver fibrosis and cirrhosis. In the present study, we took advantage of a transgenic mouse (TG221) characterized by microRNA-221 overexpression, with cirrhotic liver background induced by chronic administration of carbon tetrachloride (CCl4). This mouse model develops fibrosis, cirrhosis and liver tumours that become visible in 100% of mice at 5–6 months of age. Our results demonstrated that metformin intervention improves liver function, inhibits hepatic stellate cell (HSC) activation, reduces liver fibrosis, depletes lipid accumulation in hepatocytes, halts progression to decompensated cirrhosis and abrogates development HCC in CCl4 challenged transgenic mouse model. The study establishes the rationale for investigating metformin in cirrhotic patients regardless of concomitant DM2 status.

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Acknowledgements

This work was supported by the Italian Association for Cancer Research (AIRG IG-15615, AIRC IG-20055) to Massimo Negrini, PhD.

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Authors and Affiliations

  1. Department of Morphology Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

    Ram C. Shankaraiah, Elisa Callegari, Paola Guerriero, Alessandro Rimessi, Paolo Pinton & Massimo Negrini

  2. Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138, Bologna, Italy

    Laura Gramantieri

  3. Section of Anatomy and Pathology, University Hospital of Parma, Parma, Italy

    Enrico M. Silini

  4. Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy

    Silvia Sabbioni

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  1. Ram C. Shankaraiah
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Shankaraiah, R.C., Callegari, E., Guerriero, P. et al. Metformin prevents liver tumourigenesis by attenuating fibrosis in a transgenic mouse model of hepatocellular carcinoma. Oncogene 38, 7035–7045 (2019). https://doi.org/10.1038/s41388-019-0942-z

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