Abstract 4778: Dissecting the gender disparity of hepatocellular carcinoma: roles of HBV X protein and androgen receptor.

Abstract

Hepatocellular carcinoma (HCC) is a leading cancer worldwide and especially prevalent in Southeast Asia, due to prevalent hepatitis B virus (HBV) infection. HBV-associated HCC has a male predominance, with a male-to-female ratio of about 4-5:1. HBV is a partially double-stranded DNA virus containing four overlapping open reading frames. Among them, X gene is most frequently integrated into host genome naturally and plays an important role in hepatocarcinogenesis. In male HBV carriers, the risk of HCC development is significantly increased in those with higher serum androgen and androgen receptor (AR) activity. HBV infection may, therefore, particularly cooperate with male-specific AR signalling to accelerate hepatocarcinogenesis. In this study, we hypothesized that HBx cooperated with male-specific AR signalling to enhance hepatocarcinogenesis, and natural HBx truncated mutants exerted different effects on this AR signalling. Firstly, we demonstrated that the expression of androgen receptor was significantly higher in the HCC cells when compared to the immortalized non-tumorigenic normal liver cell lines (LO2 and MIHA). Moreover, the HCC cell lines with higher metastatic potential (MHCC-97L, MHCC-97M and LM3) had a higher AR protein expression level, suggesting a role of AR in HCC development and progression. In human HBV-associated HCC tissues, we found that the natural COOH-terminal truncated HBx was more frequently detectable in HCC tumors from male than female patients (43% and 11%, respectively). Here, we also showed that the natural COOH-terminal HBx truncated mutants HBx ΔC3 (1-95 a.a) and HBx ΔC4 (1-89a.a) physically interacted with AR, indicating the possibility of HBx ΔC3 and HBx ΔC4 in regulating AR activity and the binding of HBx with AR at its N-terminal part. Furthermore, we demonstrated that HBx truncated mutants localized in the nuclear fraction, unlike the full-length HBx protein which localized in the cytoplasm. The capability of the nuclear translocation may suggest a role of the HBx truncated mutants in regulating AR transcriptional activity. In addition, androgen induced the expression of GADD45, a DNA damage-inducible gene, in HCC cells. The androgen-induced GADD45 expression was even higher with the co-expression of full-lengthen HBx protein, demonstrating a synergistic effect between HBx and AR in inducing DNA damage and genetic instability in HCC cells. Taken altogether, these findings may provide a linkage between HBx, AR signaling, genomic instability and HCC carcinogenesis Citation Format: Yung Tuen Chiu, Irene Oi Lin Ng. Dissecting the gender disparity of hepatocellular carcinoma: roles of HBV X protein and androgen receptor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4778. doi:10.1158/1538-7445.AM2013-4778