雄激素受体增强乙型肝炎病毒整合或启动子区点突变后的肝TE

StephenW

Androgen Receptor Enhances Hepatic TERT Transcription after Hepatitis B Virus Integration or Point Mutation in Promoter Region
Chiao‐Ling Li
Chen‐Yu Li
You‐Yu Lin
Ming‐Chih Ho
Ding‐Shinn Chen
Shiou‐Hwei Yeh
Pei‐Jer Chen
First published: 02 August 2018
https://doi.org/10.1002/hep.30201

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.30201


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.

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StephenW

雄激素受体增强乙型肝炎病毒整合或启动子区点突变后的肝TERT转录
李巧玲
李晨宇
你 - 玉林
何明智
陈丁新
Shiou-Hwei Yeh
Pei-Jer Chen
首次发表：2018年8月2日
https://doi.org/10.1002/hep.30201

本文已被接受发布并经过完整的同行评审，但尚未通过编辑，排版，分页和校对过程，这可能导致此版本与记录版本之间存在差异。请引用本文为doi：10.1002 / hep.30201


抽象

肝细胞癌（HCC）的性别差异在乙型肝炎病毒（HBV）相关病例中最为显着。大多数此类HCC病例包含整合的HBV，并且一些热点整合（例如TERT启动子中的那些）激活基因表达以驱动癌发生。由于HBV基因组包含雄激素和雌激素反应基序，我们假设整合的HBV DNA对下游基因表达产生类似的调节，从而导致男性对HCC的易感性。为了验证这一假设，使用捕获 - 下一代测序（NGS）平台在101个HBV相关的HCC病例中分析了HBV整合位点以及TERT启动子和TP53编码区中的常见突变。结果显示，以相互排斥的方式发生的TERT启动子区域的HBV整合和-124G> A突变在男性中比在女性HCC中更常见（整合：22/58男性HCC，6/36女性HCC） ，P = 0.0285; -124G> A：17/62雄性HCC，3/39雌性HCC，P = 0.0201;组合，39/62雄性HCC，9/39雌性HCC，P <0.0001）。使用报告基因测定研究了性激素途径对具有遗传变化的TERT表达的影响。 TERT启动子中的HBV整合使TERT转录对性激素有反应，雄激素受体（AR）增强但雌激素受体抑制，两者都依赖于HNF4α。此外，AR还通过以GABPA依赖性方式靶向TERT启动子突变来增加TERT表达。
结论

通过整合的HBV和TERT启动子区域的点突变，AR的TERT升高被确定为HBV相关HCC的男性优势的新机制。因此，端粒酶和AR成为HCC干预的新靶点。

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