Mechanism of viral hepatitis-mediated hepatocarcinogenes

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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. Our earlier studies indicated that HBx may directly interfere with cellular functions, such as p53-mediated pathways. Because HBx contains hydrophobic leucine-rich nuclear export sequences (NES), recognized by the Crm1/Ran complex, we hypothesized that HBx may modulate certain cellular functions through its interaction with the Crm1/Ran complex. Recently, we demonstrated that HBx contains a functional NES motif and interfere with the Crm1/Ran-dependent nucleocytoplasmic transport pathway, which then activates NFkB signaling. We also elucidated a novel function of Crm1 in regulating centrosome duplication and spindle assembly, and discovered a mechanism for HBV/HBx to induce aberrant centriole duplication, leading to multipolar spindles. In addition, we demonstrated a HBV/HBx-dependent activation of RanBP1, a Ran-binding protein that is known to destabilize the Crm1/Ran 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 studies led us to generate a novel hypothesis that, analogous to the importin-Ran-NuMA-TPX2 complex in regulating microtubule nucleation during spindle assembly, the Crm1/Ran complex binds to an NES motif-containing protein to maintain centrosome integrity to insure bipolar spindles. We have developed an in vivo system that may allow us to identify cellular partners involved in this pathway. The identification of such a partner(s) may help further contribute to the mechanisms of how the fidelity of centrosome duplication is regulated and how HBV induces genomic instability and neoplastic transformation.