HBx-induced androgen receptor expression in HBV-associated hepatocarcinoma is independent of the methylation status of its promoter
Rong Zhu1*, Jian-Sheng Zhang2*, Ya-Zhen Zhu1, Jia Fan3, Yi Mao4, Qi Chen1 and Hong-Guang Zhu1
1Departments of Pathology, Shanghai Medical College, 2Departments of Epidemiology, School of Public Health, 3Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China and 4State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China
* These authors contributed equally to this work.
Offprint requests to: Rong Zhu, PhD, Department of Pathology, Shanghai Medical College, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China. e-mail: zhurongss@fudan.edu.cn
Summary. A remarkable feature of HBV-associated HCC is male predominance. The cooperation of hepatitis B virus X protein (HBx) with androgen receptor (AR) signaling pathway has been documented to contribute to this dominance. HBx, a multifunctional viral regulator, has been documented to induce promoter hypermethylation and low expression of tumor suppressor genes via activation of DNA methyl-transferase (DNMT) in hepatocarcinogenesis. In prostate cancer, hypermethylation of AR promoter is associated with loss of AR expression. However, the relationship among HBx, DNMTs, the methylation status of AR and AR expression in HBV-associated HCC is still unknown. In this report, we found that HBx correlated with high levels of AR in HCC cases and induced AR expression by stimulating its transcription in liver cell lines. HBx correlated with high expression of DNMTs in HCC cases too. Both in vivo and in vitro, however, the expression of AR was not associated with its promoter methylation status, and the methylation status of AR was not regulated by DNMTs. AR expression is higher in peritumoral tissues than in tumors, as well as being higher in HBV-associated HCC than in HBV-negative cases. Therefore, HBx-induced high expression of AR plays a role during hepatocarcinogenesis, but is not involved with its promoter methylation or DNMTs. HBx-mediated DNMT deregulation is gene-specific, and the expression and methylated regulation of AR is tissue-specific. Histol Histopathol 26, 23-35 (2011)
Key words: Androgen receptor, Hepatitis B virus, Hepatocellular carcinoma, X protein, DNA methyltransferase
DOI: 10.14670/HH-26.23