Prognostic Liver Signature profiles of Jc1-infected Huh7.5.1dif cells treated with various drugs

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide, indicating urgent need for preventive strategies. Cancer chemoprevention discovery is challenged by the absence of tractable and clinically relevant human model systems and the complex cell circuits supporting carcinogenesis. Here, we developed a simple and robust human liver cell-based system in which persistent hepatitis B/C virus infection or ethanol induce an HCC risk signature robustly predicting long-term HCC risk in cirrhotic patients. Using a computationally enriched small molecule cell-based screen followed by ex/in vivo validation in human liver tissues and animal models, we identified captopril as an HCC chemopreventive agent that antagonizes the EGF/EGFR pathway, a key driver of liver disease and hepatocarcinogenesis. Our system, modeling the cell circuits encoded in the clinical HCC risk signature, enables fast-track cancer chemoprevention discovery and provides an urgently needed approach for improving the dismal prognosis of patients at risk of HCC. DMSO-differentiated Huh7.5.1 cells (Huh7.5.1dif) were exposed to mock or HCV Jc1 clone, then treated with various drugs to measure modulation of Prognostic Liver Signature genes.