Metformin reverses a precancerous niche featuring cytoplasmic p21WAF1/CIP1-expressing hepatocytes and prevents hepatocellular carcinoma development

Prevention and treatment options for hepatocellular carcinoma (HCC) are presently limited, underscoring the necessity for elucidating molecular mechanisms underlying HCC development and identifying new prevention and therapeutic targets. We demonstrate a unique precancerous niche that features enhanced p53 pathway, aberrant cytoplasmic p21WAF1/CIP1-expressing hepatocytes, and increased CD8+ T lymphocyte and macrophage infiltration in the livers of Ncoa5+/- mouse model of HCC. Metformin treatment reverses these precancerous features and profoundly reduces tumor incidence. Our data also reveal that a subset of HCC patients with a similar precancerous niche in the adjacent noncancerous livers had a relatively poor prognosis. Our study suggests a perceptible hepatic niche predisposing to HCC development and uncovers new actions of metformin in the prevention and treatment of HCC. Overall design: Liver mRNA profiles of a cohort of 20 week old C57BL/6 mice were generated by Illumina HiSeq2500, samples include 4 Ncoa5+/- and 4 wild type mice which were not treated by metformin. Liver mRNA profiles of another cohort of 39 week old C57BL/6 mice were generated by Illumina HiSeq4000. Part of the cohort of 39 week old mice includes 5 Ncoa5+/- mice and 3 wild type mice treated with Metformin through drinking water for 31 weeks, the rest of 39 week old cohort are 5 non-treated Ncoa5+/- mice and 4 non-treated wild type mice.