1-7-bis(4-hydroxy-3-methoxyphenyl)-1-4-6-heptatrien-3-one and Hepatitis-B

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.

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Agents; Base Sequence; Carcinoma, Hepatocellular; Cell Transformation, Viral; Curcumin; Diethylnitrosamine; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Hepatitis B; Hepatitis B virus; Humans; Liver; Liver Neoplasms; Male; Mice; Mice, Knockout; Mice, Transgenic; Molecular Sequence Data; Promoter Regions, Genetic; Receptors, Androgen; RNA, Viral; Time Factors; Transcription, Genetic; Transfection; Tumor Burden; Viral Load