Hepatocellular carcinoma (HCC) is a deadly disease with limited systemic therapy options and sharply increasing incidence rates in developed regions of the world. Prevention is essential to reduce HCC mortality rates, however chemopreventive agents are lacking. The first-line, type two diabetes drug, metformin, shows promise as an HCC preventive, but mechanisms of action are not fully understood. We use the Ncoa5+/- mouse model of HCC to demonstrate critical gene expression changes in the preneoplastic mouse liver that also correlate with human NCOA5 expression in HCC and HCC-adjacent tissues. Inflammatory and p53 pathways display upregulated expression in Ncoa5+/- liver, as well as cytoplasmic p21WAF1. Long term metformin treatment dramatically reduced tumor incidence in the Ncoa5+/- mouse model and reduced aberrant cytoplasmic p21WAF1-positive hepatocytes. We also identified a subgroup of human HCC patients whose HCC-adjacent tissue displayed a distinct pattern of inflammation pathway enrichment and high CDKN1A (p21WAF1) gene expression, similar to the preneoplastic Ncoa5+/- mouse liver. Gene expression changes elicited by metformin are predicted to reduce p21WAF1 liver expression in humans. Our study suggests a molecular mechanism underlying HCC development and uncovers new actions for metformin in the prevention of HCC.
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