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。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含有由Crm 1/Ran复合物识别的疏水性富亮氨酸核输出序列（内斯），我们假设HBx可能通过与Crm 1/Ran复合物的相互作用调节某些细胞功能。最近，我们发现HBx含有一个功能性的内斯基序，并干扰Crm 1/Ran依赖的核质转运途径，然后激活NF κ B信号。我们还阐明了Crm 1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诱导异常中心粒复制，导致多极纺锤体的机制。此外，我们证明了HBV/HBx依赖性激活RanBP 1，RanBP 1是一种已知使Crm 1/Ran复合物不稳定的Ran结合蛋白。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。这些研究使我们产生了一个新的假设，类似于importin-Ran-NuMA-TPX 2复合物在纺锤体组装过程中调节微管成核，Crm 1/Ran复合物结合到含有内斯基序的蛋白质以维持中心体的完整性，从而确保双极纺锤体。我们已经开发了一种体内系统，可以让我们确定参与这一途径的细胞伙伴。这种伴侣的鉴定可能有助于进一步促进中心体复制的保真度如何调节以及HBV如何诱导基因组不稳定性和肿瘤转化的机制。

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.