Metformin Prevents Liver Tumourigenesis by Attenuating Fibrosis in a Transgenic Mouse Model of Hepatocellular Carcinoma

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2019 Aug 15

PMID 31409896

Citations 36

Authors

Ram C Shankaraiah

Elisa Callegari

Paola Guerriero

Alessandro Rimessi

Paolo Pinton

Laura Gramantieri

Enrico M Silini

Silvia Sabbioni

Massimo Negrini

Affiliations

Soon will be listed here.

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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