Gene expression profiles of Huh7.5.1 and HepG2 cells infected with HCV, HBV, HDV, and alcohol, and clinical liver tissues treated with various compounds of co-culture with LX2 cells. Homo sapiens

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death. Curative approaches are limited and chemoprevention is not available. A 186-gene signature in liver tissue predicts HCC risk in cirrhotic patients of various etiologies. However, the drivers of the HCC risk gene signature remain to be fully elucidated. Here, we develop a simple and robust liver cell-based system in which persistent hepatitis B and C virus infection or ethanol exposure induce this signature. We identified candidate drivers of the HCC high-risk signature and hepatocarcinogenesis and uncovered reversal of the signature by an EGFR inhibitor and pioglitazone, a computationally predicted inhibitory compound. This cell-based model unravels the cell circuits of liver disease progression and identifies HCC chemoprevention targets for clinical evaluation. Overall design: DMSO-differentiated Huh7.5.1 cells, HepG2-NTCP cells, Huh7.5.1-NTCP cells, or clinical liver tissue slices were exposed to mock, HCV, HBV, or EtOH, and treated with variety of compounds or co-culture with hepatic stellate cell line, LX2. After 2 to 10 days of culture, cells/tissues were harvested for RNA isolation and gene expression profiling by NanoString assay.