Mechanism of viral hepatitis-mediated hepatocarcinogenesis

我们先前的结果表明，HBx含有一个功能性的核输出信号基序，该基序利用了RAN/CRM1复合体，这是许多细胞和病毒蛋白核质运输中必不可少的成分。我们证明HBX不仅使用并破坏依赖RAN/CRM1的活动，可能是为了防止宿主的抗病毒反应。这一发现表明RAN/CRM1复合体参与了乙肝病毒的分子发病机制。最近，我们发现了RAN/CRM1复合体在调控细胞蛋白中的一个新角色，该蛋白控制中心体复制和有丝分裂纺锤体组装。我们发现核磷蛋白是RAN/CRM1的一种新的底物，可以负向调节不必要的中心体复制。此外，我们还证明了一种依赖于乙肝病毒/HBx的RanBP1的激活，RanBP1是一种已知的使RAN/CRM1复合体不稳定的RAN结合蛋白。在乙肝病毒阳性的肝组织和肝细胞癌中也可以观察到RanBP1的升高。RanBP1的表达增加导致多极纺锤体和异常有丝分裂。因此，乙肝病毒/HBx的共同作用导致了染色体的不稳定。这些发现导致我们产生了一个新的假说，即RAN/CRM1复合体通过提供控制细胞内稳态的加载对接机制作为中心体复制检查点，而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，我们最近还完成了一项初步研究，确定了B淋巴细胞中与丙型肝炎病毒核心相关的基因表达谱。我们发现，丙型肝炎病毒核心蛋白可能通过选择性地抑制与抗原呈递有关的基因而驱逐免疫。这些研究有助于剖析在肝癌发生过程中必不可少的病毒活动。

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.