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

Abstract

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.

• Authors: Chi-Ming Chiu, Shiou-Hwei Yeh, Pei-Jer Chen, Ti-Jung Kuo, Ching-Ju Chang, Po-Jen Chen, Wan-Jen Yang, Ding-Shinn Chen
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 8 Pg. 2571-8 (Feb 20 2007) ISSN: 0027-8424 [Print] United States
• PMID: 17259306 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Androgens (metabolism, pharmacology)
• Animals
• Cell Line, Transformed
• Cell Nucleus (drug effects, metabolism)
• Cytosol (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Gene Expression Regulation
• Hepatitis B
• Hepatitis B virus (metabolism)
• Hepatocytes (drug effects, 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, genetics, metabolism)
• Stem Cells
• Trans-Activators (chemistry, metabolism)
• Viral Regulatory and Accessory Proteins