Androgen Receptor Enhances Hepatic Telomerase Reverse Transcriptase Gene Transcription After Hepatitis B Virus Integration or Point Mutation in Promoter Region
Journal
Hepatology
Journal Volume
69
Journal Issue
2
Pages
498-512
Date Issued
2019
Author(s)
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 telomerase reverse transcriptase gene (TERT) promoter, activate gene expression to drive carcinogenesis. As the HBV genome contains both androgen-responsive 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 the common mutations in the TERT promoter and tumor protein P53 (TP53) coding region were analyzed in 101 HBV-related HCC cases using a capture-next-generation sequencing 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 in female patients with HCC (integration: 22/58 male patients with HCC, 6/36 female patients with HCC, P = 0.0285; –124G>A: 17/62 male patients with HCC, 3/39 female patients with HCC, P = 0.0201; in combination, 39/62 male patients with HCC, 9/39 female patients with HCC, 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 the 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 hepatocyte nuclear factor 4 alpha. Besides, AR also increased TERT expression by targeting TERT promoter mutations in a GA binding protein transcription factor subunit alpha–dependent manner. Conclusion: TERT elevation by AR through integrated HBV and point mutation at the TERT promoter region was identified as a mechanism for the male dominance of HBV-related HCCs; telomerase and AR thus may be targets for intervention of HCC. ? 2018 by the American Association for the Study of Liver Diseases.
Other Subjects
androgen; androgen receptor; DNA fragment; estrogen; estrogen receptor; GA binding protein; genomic DNA; hepatocyte nuclear factor 4alpha; protein p53; telomerase reverse transcriptase; virus DNA; androgen; androgen receptor; estrogen; GA binding protein; telomerase; TERT protein, human; alpha chain; Article; DNA hybridization; DNA integration; DNA probe; estrogen responsive element; female; gene expression; gene mutation; genetic transcription; hepatitis B; Hepatitis B virus; human; human tissue; liver cell carcinoma; liver tissue; major clinical study; male; next generation sequencing; nonhuman; point mutation; priority journal; promoter region; RNA extraction; sex difference; somatic mutation; virus DNA cell DNA interaction; whole genome sequencing; comparative study; complication; gene expression regulation; genetics; Hepatitis B virus; high throughput sequencing; liver tumor; metabolism; oncogene; physiology; point mutation; promoter region; sexual characteristics; virus DNA cell DNA interaction; Androgens; Carcinoma, Hepatocellular; Estrogens; Female; GA-Binding Protein Transcription Factor; Gene Expression Regulation, Neoplastic; Hepatitis B; Hepatitis B virus; High-Throughput Nucleotide Sequencing; Humans; Liver Neoplasms; Male; Oncogenes; Point Mutation; Promoter Regions, Genetic; Receptors, Androgen; Sex Characteristics; Telomerase; Virus Integration
Publisher
John Wiley and Sons Inc.
Type
journal article