Hepatology. 2018 Aug 2. doi: 10.1002/hep.30201. [Epub ahead of print]
Androgen Receptor Enhances Hepatic TERT Transcription after Hepatitis B Virus Integration or Point Mutation in Promoter Region.
Li CL1, Li CY1, Lin YY2, Ho MC3, Chen DS2,4, Yeh SH1,5,6, Chen PJ2,4,5.
Author information
1
Department of Microbiology.
2
Graduate Institute of Clinical Medicine.
3
Department of Surgery.
4
Department of Internal Medicine.
5
National Taiwan University Center for Genomic Medicine.
6
Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Abstract
The gender disparity of hepatocellular carcinoma (HCC) is most striking in hepatitis B virus (HBV)-related cases. The majority of such HCC cases contain integrated HBV, and some hotspot integrations, such as those in the TERT promoter, activate gene expression to drive carcinogenesis. As the HBV genome contains both androgen- and estrogen-responsive motifs, we hypothesized that the integrated HBV DNA renders a similar regulation for downstream gene expression and thus contributes to male susceptibility to HCC. To test this hypothesis, the HBV integration sites, and also the common mutations in the TERT promoter and TP53 coding region, were analyzed in 101 HBV-related HCC cases using a capture-next-generation sequencing (NGS) platform. The results showed that both HBV integration and -124G>A mutation in the TERT promoter region, occurring in a mutually exclusive manner, were more frequent in male than those in female HCCs (integration: 22/58 male HCCs, 6/36 female HCCs, P=0.0285; -124G>A: 17/62 male HCCs, 3/39 female HCCs, P=0.0201; in combination, 39/62 male HCCs, 9/39 female HCCs, P<0.0001). The effects of sex hormone pathways on the expression of TERT with both genetic changes were investigated using a reporter assay. HBV integration in TERT promoter rendered the TERT transcription responsive to sex hormones, with enhancement by androgen receptor (AR) but suppression by estrogen receptor, both of which were dependent on HNF4α. Besides, AR also increased TERT expression by targeting TERT promoter mutations in a GABPA-dependent manner.
CONCLUSION:
TERT elevation by AR via integrated HBV and point mutation at TERT promoter region was identified as a new mechanism for the male dominance of HBV-related HCCs. Telomerase and AR thus become new targets for intervention of HCC. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
KEYWORDS:
Gender difference; Hepatitis B virus integration; Hepatocellular carcinoma; Sex hormone; TERT promoter mutation