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bioRxiv · 10.1101/2020.08.08.241661

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

Scott, J.·Liu, S.·Klatt, K.·Sun, Z.·Guo, Q.·Grimm, S.·Coarfa, C.·Dong, B.·Moore, D. D.
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Abstract

Background and AimsThe xenobiotic nuclear receptor Constitutive Androstane Receptor (CAR) is essential for xenobiotic tumor promotion in mouse models. In these models, {beta}-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 {beta}-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 {beta}-catenin activation. Approach and ResultsWe 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 {beta}-catenin nuclear localization and upregulation of {beta}-catenin targets. The {beta}-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. ConclusionsActivation of CAR in the presence of HBx results in tumors with strong {beta}-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.

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Scott, J., Liu, S., Klatt, K., Sun, Z., Guo, Q., Grimm, S., Coarfa, C., Dong, B., Moore, D. D.. 2020-08-10. Constitutive Androstane Receptor and Hepatitis B Virus X Protein Cooperatively Induce β-catenin-Activated Liver Tumors. https://doi.org/10.1101/2020.08.08.241661

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