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.

超过85％的HCC病例全球保留HBV和HCV的标记，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编码致癌蛋白。例如，HBV的HBX和HCV的P21核在转基因小鼠中具有致癌性，这表明这些蛋白质可能在肝炎介导的肝癌发生中起着直接的作用。我们的早期研究表明，HBX可能直接干扰细胞功能，例如p53介导的途径。由于HBX含有CRM1/RAN复合物识别的疏水亮氨酸核出口序列（NES），因此我们假设HBX可以通过与CRM1/RAN复合物的相互作用来调节某些细胞功能。最近，我们证明了HBX包含功能性NES基序，并干扰CRM1/RAN依赖性核总质传输途径，然后激活NFKB信号传导。我们还阐明了CRM1在调节中心体重复和主轴组件中的新功能，并发现了HBV/HBX诱导异常中心复制的机制，从而导致多极了纺锤体。此外，我们证明了RANBP1的HBV/HBX依赖性激活，RANBP1是一种结合蛋白，已知可破坏CRM1/RAN复合物的稳定性。在HBV阳性肝组织和HCC中也观察到RANBP1升高。 RANBP1的表达增加会导致多极纺锤体和异常有丝分裂。因此，HBV/HBX的综合作用有助于染色体不稳定性。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复合物在调节纺锤体组装过程中的微管成核方面类似，CRM1/RAN复合物与NES基序的蛋白质结合，以维持中心体的完整性以确保双极链球夹层。我们已经开发了一个体内系统，该系统可能使我们能够识别涉及该途径的细胞伴侣。这种伴侣的识别可能有助于进一步促进中心体重复的保真度调节以及HBV如何诱导基因组不稳定性和肿瘤转化的机制。