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

Sci Transl Med. 2010 May 19;2(32):32ra35. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • RNA, Viral / metabolism*
  • Receptors, Androgen / deficiency
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Time Factors
  • Transcription, Genetic*
  • Transfection
  • Tumor Burden
  • Viral Load


  • 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one
  • Androgen Receptor Antagonists
  • Antineoplastic Agents
  • RNA, Viral
  • Receptors, Androgen
  • Diethylnitrosamine
  • Curcumin