Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Androgen Receptor Antagonists
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Animals
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Antineoplastic Agents / pharmacology
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Base Sequence
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Carcinoma, Hepatocellular / chemically induced
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / prevention & control
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Carcinoma, Hepatocellular / virology*
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Cell Transformation, Viral / genetics
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Curcumin / analogs & derivatives
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Curcumin / pharmacology
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Diethylnitrosamine
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Disease Models, Animal
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Gene Expression Regulation, Neoplastic*
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Hep G2 Cells
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Hepatitis B / complications
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Hepatitis B / genetics*
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Hepatitis B virus / genetics*
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Humans
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Liver / metabolism
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Liver / pathology
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Liver / virology*
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Liver Neoplasms / chemically induced
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / prevention & control
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Liver Neoplasms / virology*
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Male
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Mice
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Mice, Knockout
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Mice, Transgenic
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Molecular Sequence Data
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Promoter Regions, Genetic
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RNA, Viral / metabolism*
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Receptors, Androgen / deficiency
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism*
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Time Factors
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Transcription, Genetic*
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Transfection
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Tumor Burden
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Viral Load
Substances
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1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one
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Androgen Receptor Antagonists
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Antineoplastic Agents
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RNA, Viral
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Receptors, Androgen
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Diethylnitrosamine
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Curcumin