Mechanism of viral hepatitis-mediated hepatocarcinogenes

病毒性肝炎介导的肝癌机制

• 批准号: 7048109
• 负责人: XIN WEI WANG
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7048109
• 关键词: binding proteins; biological signal transduction; cell cycle; cell growth regulation; gene expression; hepatitis B virus group; hepatitis C virus; hepatocellular carcinoma; human tissue; liver neoplasms; neoplasm /cancer epidemiology; nuclear factor kappa beta; oncoproteins; p53 gene /protein; protein protein interaction; protein structure function; tissue /cell culture; viral carcinogenesis; virus protein; virus related neoplasm /cancer

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.

全世界超过85%的肝细胞癌患者保留了乙肝病毒和丙型肝炎病毒的标志物，这表明乙肝病毒和丙型肝炎病毒是肝细胞癌的主要病原体。除了引起慢性炎症和细胞死亡-再生周期外，乙肝病毒和丙型肝炎病毒还编码致癌蛋白。例如，乙肝病毒的HBx和丙型肝炎病毒的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发挥直接作用。我们早期的研究表明，HBx可能直接干扰细胞功能，如P53介导的通路。由于HBx含有CRM1/RAN复合体识别的疏水性富含亮氨酸的核输出序列(NES)，我们推测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含有一个功能性的NES基序，并干扰依赖CRM1/RAN的核质转运途径，进而激活NFkB信号转导。我们还阐明了CRM1在调节中心体复制和纺锤体组装中的一个新功能，并发现了HBVHBx诱导中心粒异常复制导致多极纺锤体的机制。此外，我们还证明了一种依赖于乙肝病毒/HBx的RanBP1的激活，RanBP1是一种已知的破坏CRM1/RAN复合体稳定的RAN结合蛋白。在乙肝病毒阳性的肝组织和肝细胞癌中也可以观察到RanBP1的升高。RanBP1的表达增加导致多极纺锤体和异常有丝分裂。因此，乙肝病毒/HBx的共同作用导致了染色体的不稳定。这些研究导致我们产生了一个新的假设，即类似于Importin-RAN-NUMA-TPX2复合体在纺锤体组装过程中调节微管成核，CRM1/RAN复合体与含有NES基序的蛋白质结合，以保持中心体的完整性，以确保双极纺锤体。我们已经开发了一个体内系统，可以让我们识别参与这一途径的细胞伙伴。这种伙伴(S)的发现可能有助于进一步研究中心体复制的保真度是如何调节的，以及乙肝病毒如何诱导基因组不稳定和肿瘤转化的机制。