Constitutive Androstane Receptor and Hepatitis B Virus X Protein Cooperatively Induce β-catenin-Activated Liver Tumors

Abstract

Background and Aims: The xenobiotic nuclear receptor Constitutive Androstane Receptor (CAR) is essential for xenobiotic tumor promotion in mouse models. In these models, β-catenin is genetically activated in approximately 80% of tumors. Chronic Hepatitis B Virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC), and β-catenin activation is also frequently activated in HBV-associated HCCs. The goal of this research was to determine whether activation of CAR in a mouse model of chronic HBV infection would result in tumor formation and whether these tumors would display increased β-catenin activation. Approach and Results: We treated transgenic mice expressing the HBV X protein (HBx) in hepatocytes with a single dose of the potent CAR agonist TCPOBOP. After 10 months, these mice developed large liver tumors that are characterized by β-catenin nuclear localization and upregulation of β-catenin targets. The β-catenin regulator FoxM1 and the oxidative stress master regulator Nrf2, both of which are CAR gene targets, were also overactivated in tumors. The CAR/HBx tumors share a conserved gene signature with HBV-related human hepatocellular carcinoma. Conclusions: Activation of CAR in the presence of HBx results in tumors with strong β-catenin activation. The mouse model we have described reflects the gene expression patterns seen in human HBV-associated HCC and presents an attractive basis for future studies.