Mechanism of viral hepatitis-mediated hepatocarcinogenes

全球85%以上的HCC病例保留HBV和HCV标记物，表明HBV和HCV是HCC的主要病因。除了引起慢性炎症和细胞死亡再生周期外，HBV和HCV还编码致癌蛋白。例如，HBV和HCV核心的HBx在转基因小鼠中是致癌的，这表明这些蛋白可能在肝炎介导的肝癌发生中起直接作用。由于病毒是发现人类致癌关键途径的宝贵工具，我们最初的研究重点是HBx和HCV核心的分子方面。我们之前的研究结果表明，HBx含有一个功能性核输出信号基元，该基元利用Ran/Crm1复合物，这是许多细胞和病毒蛋白的核胞质运输所必需的成分。我们证明HBx不仅使用而且破坏Ran/ crm1依赖的活性，可能是为了阻止宿主的抗病毒反应。这一发现暗示Ran/Crm1复合体参与HBV的分子发病机制。最近，我们发现了Ran/Crm1复合体在调节控制中心体复制和有丝分裂纺锤体组装的细胞蛋白中的新作用。我们发现核蛋白是Ran/Crm1负性调节不必要的中心体复制的新底物。此外，我们还证明了HBV/ hbx依赖性的RanBP1激活，RanBP1是一种已知可以破坏Ran/Crm1复合物稳定性的Ran结合蛋白。在hbv阳性的肝组织和HCC中也观察到RanBP1的升高。RanBP1表达增加导致多极纺锤体和有丝分裂异常。因此，HBV/HBx的联合作用导致染色体不稳定。这些发现使我们产生了一个新的假设，其中Ran/Crm1复合体通过提供控制细胞稳态的“装载码头”机制作为中心体重复检查点，并且该复合体的破坏可能导致基因组不稳定，这可能是病毒性肝炎介导的肝癌发生的早期步骤。除了HBx外，我们最近还完成了一项初步研究，确定了B淋巴细胞中HCV核心相关基因的表达谱。我们发现HCV核心可能通过选择性抑制参与抗原呈递的基因来驱逐免疫。这些研究有助于解剖在肝癌发生过程中必不可少的病毒活动。

More than 85% of HCC cases worldwide retain markers for HBV and HCV, indicating that HBV and HCV are major etiological agents for HCC. In addition to causing chronic inflammation and cell death-regeneration cycles, HBV and HCV encode oncogenic proteins. For example, HBx of HBV and HCV core are oncogenic in transgenic mice, suggesting that these proteins may play a direct role in hepatitis-mediated hepatocarcinogenesis. Because viruses have been invaluable tools for discovering key pathways for human carcinogenesis, our initial study was focusing on the molecular aspect of HBx and HCV core. Our previous results indicate that HBx contains a functional nuclear export signal motif that utilizes the Ran/Crm1 complex, a component essential in nucleocytoplasmic transport of many cellular and viral proteins. We demonstrated that HBx not only uses but also disrupts Ran/Crm1-dependent activities, presumably to prevent a host antiviral response. This finding implicates the Ran/Crm1 complex in the molecular pathogenesis of HBV. Recently, we uncovered a new role of the Ran/Crm1 complex in regulating cellular proteins that control centrosome duplication and mitotic spindle assembly. We revealed nucleophosmin as a novel substrate for Ran/Crm1 to negatively regulate unnecessary centrosome duplication. In addition, we demonstrated a HBV/HBx-dependent activation of RanBP1, a Ran-binding protein that is known to destabilize the Ran/Crm1 complex. Elevated RanBP1 is also observed in HBV-positive liver tissues and in HCC. Increased expression of RanBP1 leads to multipolar spindles and abnormal mitoses. Thus, the combined effects of HBV/HBx contribute to chromosome instability. These findings led us to generate a new hypothesis in which the Ran/Crm1 complex serves as the centrosome duplication checkpoint by providing a 'loading dock' mechanism that controls cellular homeostasis, and the disruption of this complex may result in genomic instability, which may be an early step in viral hepatitis-mediated hepatocarcinogenesis. In addition to HBx, recently we have completed a pilot study by determining HCV core-related gene expression profiles in B lymphocytes. We found that HCV core may evict immunity by selectively suppressing genes involved in antigen presentation. These studies are useful in dissecting viral activities that are essential in hepatocarcinogenesis.