Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx
Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx
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DOI：
10.1038/sj.onc.1202867
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发表时间：
1999-08-26
期刊：
影响因子：
8
通讯作者：
Bréchot, C
中科院分区：
文献类型：
--
作者：
Sirma, H;Giannini, C;Bréchot, C
乙型肝炎病毒（HBV）慢性感染是人类肝细胞癌的主要原因，有证据表明病毒反式激活因子HBx在HBV相关性肝癌的分子发病机制中起着关键作用。为了研究HBx的实际影响及其作用机制，我们最近克隆并鉴定了一组HBV慢性感染患者肝细胞癌的X序列。我们比较了HBx及其天然突变体对细胞生长和存活力的影响。我们报告HBx抑制克隆生长的细胞和诱导凋亡的p53非依赖性途径。此外，HBx的表达诱导了G1期细胞周期阻滞，然后通过凋亡进行反选择。重要的是，在肝细胞癌中HBx基因的突变消除了HBx诱导的生长停滞和凋亡。使用一组工程突变体，我们已经将HBx的生长抑制作用映射到其反式激活功能所需的结构域。基于这些结果，我们提出，废除HBx的抗增殖和凋亡作用的自然发生的突变可能会使肝细胞容易失控的增长，并有助于与HBV感染相关的多步骤肝癌。
Chronic infection by HBV is the leading cause of hepatocellular carcinoma in man. Several lines of evidence suggest that the viral transactivator HBx plays a critical role in the molecular pathogenesis of HBV-related HCC, To study the actual impact of HBx and the mechanism of its action, we have recently cloned and characterized a set of X-sequences from HCC in patients with chronic infection by HBV, In the present study, we have compared the effects of HBx and its naturally arising mutants on cell growth and viability. We report that HBx inhibits clonal outgrowth of cells and induces apoptosis by a p53-independent pathway. Furthermore, HBx expression induced a late G1 cell cycle block prior to their counterselection by apoptosis, Importantly, mutations in the HBx-gene evolving in hepatocellular carcinoma abolished both HBx-induced growth arrest and apoptosis, Using a panel of engineered mutants me have mapped the growth suppressive effect of HBx to domains shown to be required for its transactivating function. Based on these results, we propose that abrogation of the anti-proliferative and apoptotic effects of HBx by naturally occurring mutations might render the hepatocytes susceptible to uncontrolled growth and contribute to multistep hepatocarcinogenesis associated with HBV-infection.