Androgen Receptor Enhances Hepatic Telomerase Reverse... : Hepatology (original) (raw)

Original Articles: VIRAL HEPATITIS

Androgen Receptor Enhances Hepatic Telomerase Reverse Transcriptase Gene Transcription After Hepatitis B Virus Integration or Point Mutation in Promoter Region

Li, Chiao‐Ling1; Li, Chen‐Yu1; Lin, You‐Yu2; Ho, Ming‐Chih3; Chen, Ding‐Shinn2,4; Chen, Pei‐Jer2,4,5; Yeh, Shiou‐Hwei*,1,5,6

1Department of MicrobiologyNational Taiwan University College of Medicine and HospitalTaipeiTaiwan

2Graduate Institute of Clinical MedicineNational Taiwan University College of Medicine and HospitalTaipeiTaiwan

3Department of SurgeryNational Taiwan University College of Medicine and HospitalTaipeiTaiwan

4Department of Internal MedicineNational Taiwan University College of Medicine and HospitalTaipeiTaiwan

5National Taiwan University Center for Genomic MedicineNational Taiwan University College of Medicine and HospitalTaipeiTaiwan

6Department of Laboratory MedicineNational Taiwan University College of Medicine and HospitalTaipeiTaiwan

*Address Correspondence and Reprint Requests to:
Shiou‐Hwei Yeh, Ph.D., Department of Microbiology, National Taiwan University College of Medicine, No. 1, Jen‐Ai Road, Section 1, Taipei 100, Taiwan. E‐mail: [email protected]

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.