Mechanism of viral hepatitis-mediated liver carcinogenes

病毒性肝炎介导的肝癌致癌机制

• 批准号: 6558973
• 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/6558973
• 关键词: DNA repair; binding proteins; gene environment interaction; hepatitis B virus group; hepatitis C virus; hepatocellular carcinoma; human tissue; liver neoplasms; neoplasm /cancer epidemiology; structural biology; tumor suppressor genes; viral carcinogenesis; virus protein; virus related neoplasm /cancer

Cellular homeostasis is regulated tightly by the activities of many cellular proteins. The subcellular localization and stability of these proteins are critical for their activities. Examples include proteins that are transported into or out of the nucleus by specific receptors through the recognition of nuclear-localization signals (NLS) and/or nuclear export signals (NES). One recently identified NES is a short, hydrophobic, leucine-rich motif that is necessary and sufficient to mediate nuclear export of large carrier proteins and mRNAs. The activity of many cellular transcription factors, oncoproteins, cell cycle regulators and tumor suppressor proteins has been reported to be regualted by their NES. Interestingly, many viral proteins also utilize the Crm1/Ran-mediated pathway, even though some of these viral proteins are thought to be small enough to passively diffuse through the nuclear pore complex (NPC). The fact that these oncogenic viral proteins have acquired NES activity and modified nuclear export implies that nuclear export may be an efficiet target for viral-mediated oncogenesis. In this study, we are examining the hypothesis that both the X protein (HBx) of hepatitis B virus (HBV) and core protein (HC-core) of hepatitis C virus (HCV), two major risk factors for hepatocellular carcinoma, may induce neoplastic transformation by disregulating the Crm1/Ran-mediated pathways. Recently, we discovered that the HBx and HC-core proteins contain functional NESs. Unlike other cellular NES-containing proteins, HBx binds to and sequesters Crm1 in the cytoplasm, thereby modulating Crm1-mediated nuclear export of other cellular proteins including the NFkB/IkBa complex. Similarly, HC-core-mediated activation of the NFkB/IkBa complex also depends on the presence of NESs. These findings suggest that multiple cellular functions associated with HBx or HC-core may be due, in part, to their influence on the Crm1/Ran-mediated pathway. Because Crm1 and its cofactor Ran GTPase also play a key role in mitosis initiation, the inactivation of Crm1 by HBx or HC-core also may induce genomic instability. Our initial results indicate that HBx induces centrosome amplification and aberrant mitosis. These results led us to generate a novel testable hypothesis that Crm1 may be a common target for viral hepatitis-mediated oncogenicity and provide a foundation for a possible involvement of Crm1 in human carcinogenesis.

细胞内稳态受到许多细胞蛋白质活性的严格调节。这些蛋白质的亚细胞定位和稳定性对其活性至关重要。实例包括通过识别核定位信号（NLS）和/或核输出信号（内斯）由特异性受体转运入或转运出核的蛋白质。最近鉴定的一种内斯是一种短的、疏水的、富含亮氨酸的基序，其对于介导大载体蛋白和mRNA的核输出是必需的且足够的。许多细胞转录因子、癌蛋白、细胞周期调节因子和肿瘤抑制蛋白的活性都受到它们的内斯的调节。有趣的是，许多病毒蛋白也利用Crm 1/Ran介导的途径，即使这些病毒蛋白中的一些被认为是足够小的，以被动地通过核孔复合物（NPC）扩散。这些致癌病毒蛋白具有内斯活性和修饰的核输出这一事实意味着核输出可能是病毒介导的肿瘤发生的有效靶点。 在这项研究中，我们正在研究的假设，即B肝炎病毒（HBV）的X蛋白（HBx）和丙型肝炎病毒（HCV）的核心蛋白（HC-core），肝细胞癌的两个主要危险因素，可能会诱导肿瘤转化的Crm 1/RAN介导的途径失调。最近，我们发现HBx和HC核心蛋白含有功能性NES。与其他细胞内含有NES的蛋白质不同，HBx结合并隔离细胞质中的Crm 1，从而调节Crm 1介导的其他细胞蛋白质（包括NFkB/IkBa复合物）的核输出。类似地，HC核心介导的NF κ B/IkBa复合物的活化也取决于NES的存在。这些发现表明，与HBx或HC核心相关的多种细胞功能可能部分是由于它们对Crm 1/Ran介导的通路的影响。由于Crm 1及其辅因子Ran GT3在有丝分裂起始中也起关键作用，因此Crm 1被HBx或HC-核心灭活也可能诱导基因组不稳定性。我们的初步结果表明，HBx诱导中心体扩增和异常有丝分裂。这些结果使我们产生了一个新的可检验的假设，Crm 1可能是病毒性肝炎介导的致癌性的共同目标，并为Crm 1可能参与人类致癌作用提供了基础。