Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription

• Published in: Science translational medicine 2010-05, Vol.2 (32), p.32ra35-32ra35
• Main Authors: Wu, Ming-Heng, Ma, Wen-Lung, Hsu, Cheng-Lung, Chen, Yuh-Ling, Ou, Jing-Hsiung James, Ryan, Charlotte Kathryn, Hung, Yao-Ching, Yeh, Shuyuan, Chang, Chawnshang
• Format: Article
• Language: English
• Subjects: Androgen Receptor Antagonists; Animals; Antineoplastic Agents - pharmacology; Base Sequence; Carcinoma, Hepatocellular - chemically induced; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - prevention & control; Carcinoma, Hepatocellular - virology; Cell Transformation, Viral - genetics; Curcumin - analogs & derivatives; Curcumin - pharmacology; Diethylnitrosamine; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Hepatitis B - complications; Hepatitis B - genetics; Hepatitis B virus - genetics; Humans; Liver - metabolism; Liver - pathology; Liver - virology; Liver Neoplasms - chemically induced; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - prevention & control; Liver Neoplasms - virology; Male; Mice; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; Promoter Regions, Genetic; Receptors, Androgen - deficiency; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; RNA, Viral - metabolism; Time Factors; Transcription, Genetic; Transfection; Tumor Burden; Viral Load
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.3001143

Hepatitis B virus (HBV)-induced hepatitis and carcinogen-induced hepatocellular carcinoma (HCC) are associated with serum androgen concentration. However, how androgen or the androgen receptor (AR) contributes to HBV-induced hepatocarcinogenesis remains unclear. We found that hepatic AR promotes HBV-induced hepatocarcinogenesis in HBV transgenic mice that lack AR only in the liver hepatocytes (HBV-L-AR(-/y)). HBV-L-AR(-/y) mice that received a low dose of the carcinogen N'-N'-diethylnitrosamine (DEN) have a lower incidence of HCC and present with smaller tumor sizes, fewer foci formations, and less alpha-fetoprotein HCC marker than do their wild-type HBV-AR(+/y) littermates. We found that hepatic AR increases the HBV viral titer by enhancing HBV RNA transcription through direct binding to the androgen response element near the viral core promoter. This activity forms a positive feedback mechanism with cooperation with its downstream target gene HBx protein to promote hepatocarcinogenesis. Administration of a chemical compound that selectively degrades AR, ASC-J9, was able to suppress HCC tumor size in DEN-HBV-AR(+/y) mice. These results demonstrate that targeting the AR, rather than the androgen, could be developed as a new therapy to battle HBV-induced HCC.