X-gene product of hepatitis B virus induces apoptosis in liver cells
X-gene product of hepatitis B virus induces apoptosis in liver cells
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DOI：
10.1074/jbc.273.1.381
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发表时间：
1998-01-02
影响因子：
4.8
通讯作者：
Yun, Y
中科院分区：
文献类型：
--
作者：
Kim, H;Lee, H;Yun, Y
乙型肝炎病毒是肝细胞癌的病原体，在肿瘤发生过程中，X基因产物（HBx）已知发挥重要作用。在这里，我们通过传统的病灶形成实验研究了 NIH3T3 细胞中 HBx 的转化潜力。将 HBx 表达质粒与其他癌基因（包括 Ha-ras、v-src、v-myc、v-fos 和 Ela）共转染。出乎意料的是，HBx的引入完全消除了所有五个测试癌基因的病灶形成能力，此外，细胞凋亡抑制剂Bcl-2的共转染逆转了HBx介导的病灶形成抑制，表明观察到的HBx对病灶形成的抑制是通过诱导细胞凋亡来实现的。接下来，为了明确测试 HBx 是否诱导肝细胞凋亡，我们建立了在四环素诱导型启动子控制下表达 HBx 的稳定 Chang 肝细胞系。在1%小牛血清存在下，这些细胞中HBx的诱导导致了典型的细胞凋亡现象，例如DNA片段化、核浓缩和片段化。基于这些结果，我们提出HBx使肝细胞在乙型肝炎病毒感染时对细胞凋亡敏感，从而促进肝炎的发展和随后的肝细胞癌的产生。
Hepatitis B virus is a causative agent of hepatocellular carcinoma, and in the course of tumorigenesis, the X-gene product (HBx) is known to play important roles. Here, we investigated the transforming potential of HBx by conventional focus formation assay in NIH3T3 cells. Cells were cotransfected with the HBx expression plasmid along with other oncogenes including Ha-ras, v-src, v-myc, v-fos, and Ela. Unexpectedly, the introduction of HBx completely abrogated the focus-forming ability of all five tested oncogenes, In addition, the cotransfection of Bcl-2, an apoptosis inhibitor, reversed the HBx-mediated inhibition of focus formation, suggesting that the observed repression of focus formation by HBx is through the induction of apoptosis. Next, to test unequivocally whether HBx induces apoptosis in liver cells, we established stable Chang liver cell lines expressing HBx under the control of a tetracycline inducible promoter. Induction of HBx in these cells in the presence of 1% calf serum resulted in typical apoptosis phenomena such as DNA fragmentation, nuclear condensation, and fragmentation, Based on these results, we propose that HBx sensitizes liver cells to apoptosis upon hepatitis B virus infection, contributing to the development of hepatitis and the subsequent generation of hepatocellular carcinoma.