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的HBx和HCV的p21core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。我们早期的研究表明，HBx可能直接干扰细胞功能，如p53介导的途径。由于HBx含有被Crm1/Ran复合体识别的疏水富含亮氨酸的核输出序列（NES），我们假设HBx可能通过与Crm1/Ran复合体的相互作用来调节某些细胞功能。最近，我们证明HBx包含一个功能性的NES基序，并干扰Crm1/ ran依赖的核胞质转运途径，然后激活NFkB信号。我们还阐明了Crm1在调节中心体复制和纺锤体组装中的新功能，并发现了HBV/HBx诱导中心粒异常复制导致多极纺锤体的机制。此外，我们证明了HBV/ hbx依赖性的RanBP1激活，RanBP1是一种已知的破坏Crm1/Ran复合物稳定的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。这些研究使我们产生了一个新的假设，即类似于在纺锤体组装过程中调节微管成核的importin-Ran-NuMA-TPX2复合体，Crm1/Ran复合体与含有NES基序的蛋白质结合以维持中心体的完整性以确保双极性纺锤体。我们已经开发了一种体内系统，可以让我们识别参与这一途径的细胞伴侣。识别这样的伴侣可能有助于进一步了解中心体复制的保真度如何受到调节以及HBV如何诱导基因组不稳定和肿瘤转化的机制。

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.