Mechanism of viral hepatitis-mediated hepatocarcinogenes

点击翻译按钮获取中文摘要

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.