1-7-bis(4-hydroxy-3-methoxyphenyl)-1-4-6-heptatrien-3-one and Liver-Neoplasms

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

Androgen effects on hepatocellular carcinoma (HCC) remain controversial and androgen ablation therapy to treat HCC also leads to inconsistent results. Here we examine androgen receptor (AR) roles in hepatocarcinogenesis using mice lacking AR in hepatocytes.. By using the Cre-Lox conditional knockout mice model injected with carcinogen, we examined the AR roles in hepatocarcinogenesis. We also tested the possible roles of AR in cellular oxidative stress and DNA damage sensing/repairing systems. By using AR degrading compound, ASC-J9, or AR-small interference RNA, we also examined the therapeutic potentials of targeting AR in HCC.. We found AR expression was increased in human HCC compared with normal livers. We also found mice lacking hepatic AR developed later and less HCC than their wild-type littermates with comparable serum testosterone in both male and female mice. Addition of functional AR in human HCC cells also resulted in the promotion of cell growth in the absence or presence of 5alpha-dihydrotestosterone. Mechanistic dissection suggests that AR may promote hepatocarcinogenesis via increased cellular oxidative stress and DNA damage, as well as suppression of p53-mediated DNA damage sensing/repairing system and cell apoptosis. Targeting AR directly via either AR-small interference RNA or ASC-J9 resulted in suppression of HCC in both ex vivo cell lines and in vivo mice models.. Our data point to AR, but not androgens, as a potential new and better therapeutic target for the battle of HCC.

Topics: Androgen Receptor Antagonists; Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; DNA Damage; DNA Repair; Female; Genes, p53; Humans; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Mice, Knockout; Mice, Nude; Oxidative Stress; Reactive Oxygen Species; Receptors, Androgen; RNA, Small Interfering; Testosterone