Mechanism of viral hepatitis-mediated hepatocarcinogenes

全世界超过85%的HCC病例保留HBV和HCV的标志物，表明HBV和HCV是HCC的主要病原体。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的HBx和HCV的p21核心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，我们最初的研究集中在HBx的分子方面，HBx是一种由B型肝炎病毒编码的病毒癌蛋白。我们发现，HBx包含一个功能性的核输出信号基序，利用Ran/Crm 1复合物，一个重要的组成部分，在核质运输的许多细胞蛋白。有趣的是，这种病毒蛋白不仅使用，而且破坏Ran/Crm 1依赖的活动，可能是为了防止宿主的抗病毒反应。这一发现暗示Ran/Crm 1复合物在HBV的分子发病机制中。这样的方法也使我们能够发现一个新的作用，Ran/Crm 1复合物在调节细胞蛋白，控制中心体复制和有丝分裂纺锤体组装，除了其在核质运输中的作用。最近，我们已经揭示了核磷蛋白作为一种新的底物Ran/Crm 1负调控不必要的中心体复制。此外，我们证明了HBV/HBx依赖性激活RanBP 1，RAN结合蛋白，已知不稳定的Ran/Crm 1复合物。在HBV阳性肝组织和HCC中也观察到RanBP 1升高。RanBP 1表达增加导致多极纺锤体和异常有丝分裂。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/Crm 1复合物通过提供控制细胞内稳态的“装载码头”机制作为中心体复制检查点，并且该复合物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。目前，我们正在探索其他潜在的合作伙伴与这个复杂的，可能会调节主轴组装。

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 p21core of HCV 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, a viral oncoprotein encoded by hepatitis B virus. We discovered that HBx contains a functional nuclear export signal motif that utilizes the Ran/Crm1 complex, a component essential in nucleocytoplasmic transport of many cellular proteins. Interestingly, this viral protein 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. Such an approach also allows us to uncover a novel role of the Ran/Crm1 complex in regulating cellular proteins that control centrosome duplication and mitotic spindle assembly, in addition to its role in nucleocytoplasmic transport. Recently, we have 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. Currently, we are exploring other potential partners associated with this complex that may regulate spindle assembly.