Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level
- Chi-Ming Chiu*,†,
- Shiou-Hwei Yeh*,
- Pei-Jer Chen†,‡,§,¶,
- Ti-Jung Kuo‡,
- Ching-Ju Chang*,
- Po-Jen Chen*,
- Wan-Jen Yang*, and
- Ding-Shinn Chen†,‡,§,¶,‖
- *Department of Microbiology,
- †Graduate Institute of Clinical Medicine,
- ‡Center for Genomic Medicine, and
- ¶Department of Internal Medicine, National Taiwan University College of Medicine, Taipei 100, Taiwan; and,
- §Hepatitis Research Center, National Taiwan University Hospital, Taipei 100, Taiwan
-
Contributed by Ding-Shinn Chen, December 4, 2006 (received for review July 27, 2006)
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.
Footnotes
- ‖To whom correspondence should be addressed. E-mail: dschen{at}ha.mc.ntu.edu.tw
-
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on May 3, 2005.
-
Author contributions: C.-M.C. and S.-H.Y contributed equally to this work; S.-H.Y., Pei-Jer Chen, and D.-S.C. designed research; C.-M.C., T.-J.K., C.-J.C., Po-Jen Chen, and W.-J.Y. performed research; C.-M.C., S.-H.Y., Pei-Jer Chen, and D.-S.C. analyzed data; and S.-H.Y., Pei-Jer Chen, and D.-S.C. wrote the paper.
-
The authors declare no conflict of interest.
- Abbreviations:
- AR,
- androgen receptor;
- HBV,
- hepatitis B virus;
- HBx,
- HBV X protein;
- HCV,
- hepatitis C virus;
- HCC,
- heptocellular carcinoma;
- DHT,
- dihydrotestosterone.
-
Freely available online through the PNAS open access option.
- © 2007 by The National Academy of Sciences of the USA
