Hepatitis B virus protein preS2 potentially promotes HCC development via its transcriptional activation of hTERT
Hepatitis B virus protein preS2 potentially promotes HCC development via its transcriptional activation of hTERT
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乙型肝炎病毒蛋白 preS2 通过 hTERT 转录激活可能促进 HCC 发展
DOI：
10.1136/gut.2008.174029
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发表时间：
2009-11-01
期刊：
影响因子：
24.5
通讯作者：
Ma, C.
中科院分区：
文献类型：
--
作者：
Luan, F.;Liu, H.;Ma, C.
背景和目的：端粒酶在B型肝炎病毒（HBV）相关的肝细胞癌（HCC）中有明显的再激活。我们的前期研究表明，HBV表面（S）基因的反式激活单元preS 2可上调HepG 2细胞端粒酶逆转录酶（hTERT）的表达和端粒酶活性。在这里，我们的目的是探索的功能，和潜在的机制，这种preS 2介导的hTERT上调在肝癌的发展。方法：采用反义核酸阻断法，对HBV转染的HepG2.2.15细胞进行阻断实验。在临床样本中检测hTERT的表达，以测试preS 2介导的hTERT上调在体内HCC发展中的作用。为了探讨preS 2介导的hTERT上调的机制，进行了共转染、报告基因分析和电泳迁移率变动分析（EMSA）。结果：阻断preS 2表达可降低HepG2.2.15细胞hTERT表达、端粒酶活性、细胞增殖和致瘤性。位于hTERT转录起始位点上游-349和-329 bp之间的区域被鉴定为负责preS 2介导的效应。preS 2与preS 2-responsible region（PRR）相互作用并激活hTERT启动子。重要的是，hTERT在preS 2阳性的人HCC样品中也高度表达。所有这些结果都有力地表明preS 2可能通过hTERT激活促进HCC的发展。结论：HBV前S2蛋白通过PRR元件上调hTERT，促进HCC的发生发展。
Backgrounds and aims: Telomerase is significantly reactivated in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). Our previous studies showed that the transactivation unit of HBV surface (S) gene, preS2, could upregulate human telomerase reverse transcriptase (hTERT) expression and telomerase activity of HepG2 cells. Here, we aim to explore the functions, and the underlying mechanisms, of this preS2-mediated hTERT upregulation during HCC development. Methods: An antisense blocking assay was performed on HBV-integrated HepG2.2.15 cells. The expression of hTERT was examined in clinical samples to test the role of the preS2-mediated hTERT upregulation in HCC development in vivo. In order to explore the mechanisms of preS2-mediated hTERT upregulation, co-transfection, reporter assays and electrophoretic mobility shift assays (EMSA) were performed. Results: Blocking preS2 expression reduced hTERT expression, telomerase activity, cell proliferation and tumorigenicity of HepG2.2.15. A region located between −349 and −329 bp upstream of the transcription initiation site of hTERT was identified as responsible for the preS2-mediated effect. preS2 interacted with the preS2-responsible region (PRR) and activated the hTERT promoter. Importantly, hTERT was also highly expressed in preS2-positive human HCC samples. All these findings strongly suggest that preS2 may promote HCC development via hTERT activation. Conclusions: HBV protein preS2 upregulates hTERT via the PRR element in promoting HCC development.