Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level

Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2571-8. doi: 10.1073/pnas.0609498104. Epub 2007 Jan 26.


Persistent hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC). One intriguing feature of HBV-related HCC is the male predominance, with a male to female ratio of 5-7:1. This dominance has been attributed to the elevated androgen level and the enhanced androgen receptor (AR)-mediated activity in the host. How HBV infection and AR signaling modulate HCC is unknown. We investigated whether the HBV nonstructural protein, X protein (HBx) could cooperate with the AR signaling pathway to enhance carcinogenesis. We found that HBx increased the anchorage-independent colony-formation potency of AR in a nontransformed mouse hepatocyte cell line. We also found that HBx functioned as a positive transcriptional coregulator to increase AR-mediated transcriptional activity. This transcription enhancement was increased in the presence of androgen in a concentration-responsive manner, thus explaining a more prominent effect in males. HBx did not physically associate with ligand-bound AR in the nucleus, and it likely augmented AR activity by increasing the phosphorylation of AR through HBx-mediated activation of the c-Src kinase signaling pathway. Our study documents HBx as a previously undescribed class of noncellular positive coregulators for AR. The results reveal a mechanism for the vulnerability of males to microbial infections and the subsequent development of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism*
  • Androgens / pharmacology
  • Animals
  • Cell Line, Transformed
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation*
  • Hepatitis B
  • Hepatitis B virus / metabolism*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Male
  • Mice
  • Models, Biological
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein Structure, Tertiary / drug effects
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Receptors, Androgen / chemistry
  • Receptors, Androgen / genetics*
  • Receptors, Androgen / metabolism*
  • Stem Cells
  • Trans-Activators / chemistry
  • Trans-Activators / metabolism*
  • Viral Regulatory and Accessory Proteins


  • Androgens
  • Receptors, Androgen
  • Trans-Activators
  • Viral Regulatory and Accessory Proteins
  • hepatitis B virus X protein
  • Proto-Oncogene Proteins pp60(c-src)