Hepatitis B Virus X Protein Blunts Senescence-Like Growth Arrest of Human Hepatocellular Carcinoma by Reducing Notch1 Cleavage
Hepatitis B Virus X Protein Blunts Senescence-Like Growth Arrest of Human Hepatocellular Carcinoma by Reducing Notch1 Cleavage
复制标题
DOI：
10.1002/hep.23613
复制
发表时间：
2010-07-01
期刊：
影响因子：
13.5
通讯作者：
Gu, Jianxin
中科院分区：
文献类型：
--
作者：
Xu, Jiejie;Yun, Xiaojing;Gu, Jianxin
慢性B型肝炎病毒（HBV）感染的严重后遗症之一是肝细胞癌（HCC）。在HBV基因组编码的所有蛋白中，B型肝炎病毒X蛋白（HBx）与HCC的发生高度相关。虽然Notch 1信号已被发现在HCC发展过程中发挥肿瘤抑制功能，但HBx表达和Notch 1信号之间的相互作用机制需要探索。在这项研究中，我们报告说，HBx在肝细胞和肝癌细胞中的表达导致内源性Notch 1胞内结构域（ICN 1）的蛋白水平和其下游靶基因的信使RNA水平降低。这些作用是由于HBx通过抑制早老素1（Psen 1）转录而不是抑制Notch 1转录或其配体的表达来减少Notch 1切割。通过瞬时HBx表达，ICN 1的减少导致体外细胞增殖增强，诱导G1-S细胞周期进展，并减缓细胞衰老。此外，在裸鼠异种移植模型中显示了通过抑制ICN 1稳定HBx表达而导致的钝化衰老样生长停滞的效果。在HBV相关的HCC患者肿瘤样本中也观察到Psen 1依赖性Notch 1信号传导抑制和钝性衰老样生长停滞的相关性。结论：我们的研究结果揭示了HBx通过减少Notch 1信号传导在钝化衰老样生长停滞中的新功能，这可能是介导HBV相关肝癌发生的假定分子机制。（肝脏学2010;52：142-154）
One of the serious sequelae of chronic hepatitis B virus (HBV) infection is hepatocellular carcinoma (HCC). Among all the proteins encoded by the HBV genome, hepatitis B virus X protein (HBx) is highly associated with the development of HCC. Although Notch1 signaling has been found to exert a tumor-suppressive function during HCC development, the mechanism of interaction between HBx expression and Notch1 signaling needs to be explored. In this study, we report that HBx expression in hepatic and hepatoma cells resulted in decreased endogenous protein levels of Notch1 intracellular domain (ICN1) and messenger RNA levels of its downstream target genes. These effects were due to a reduction of Notch1 cleavage by HBx through the suppression of presenilin1 (Psen1) transcription rather than inhibition of Notch1 transcription or its ligands' expression. Through transient HBx expression, decreased ICN1 resulted in enhanced cell proliferation, induced G1-S cell cycle progression, and blunted cellular senescence in vitro. Furthermore, the effect of blunted senescence-like growth arrest by stable HBx expression through suppression of ICN1 was shown in a nude mouse xenograft transplantation model. The correlation of inhibited Psen1-dependent Notch1 signaling and blunted senescence-like growth arrest was also observed in HBV-associated HCC patient tumor samples. Conclusion: Our results reveal a novel function of HBx in blunting senescence-like growth arrest by decreasing Notch1 signaling, which could be a putative molecular mechanism mediating HBV-associated hepatocarcinogenesis. (HEPATOLOGY 2010;52:142-154)