MECHANISM OF VIRAL HEPATITIS-MEDIATED LIVER CARCINOGENES

病毒性肝炎介导的肝癌致癌机制

• 批准号: 6435175
• 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/6435175
• 关键词: DNA repair; binding proteins; gene environment interaction; hepatitis B virus group; hepatocellular carcinoma; human tissue; neoplasm /cancer epidemiology; structural biology; tumor suppressor genes; viral carcinogenesis; 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.

细胞稳态受许多细胞蛋白的活性严格调节。这些蛋白质的亚细胞定位和稳定性对于它们的活性至关重要。例子包括通过识别核位置信号（NLS）和/或核出口信号（NES）将特定受体转运到核中或从核中输出的蛋白质。最近确定的NES是一个简短的疏水性，富含亮氨酸的基序，足以介导大型载体蛋白和mRNA的核出口所必需且足够。据报道，许多细胞转录因子，癌细胞蛋白，细胞周期调节剂和肿瘤抑制蛋白的活性已被其NES恢复。有趣的是，许多病毒蛋白也使用CRM1/RAN介导的途径，即使其中一些病毒蛋白被认为足够小，可以通过核孔复合物（NPC）被动扩散。 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肝细胞癌可能通过忽略CRM1/RAN介导的途径来诱导肿瘤转化。最近，我们发现HBX和HC核蛋白包含功能性NES。与其他含有细胞NES的蛋白不同，HBX与细胞质中的CRM1结合并隔离，从而调节CRM1介导的其他细胞蛋白的核出口，包括NFKB/IKBA复合物。同样，HC核介导的NFKB/IKBA复合物的激活也取决于NESS的存在。这些发现表明，与HBX或HC核有关的多个细胞功能可能部分归因于它们对CRM1/RAN介导的途径的影响。由于CRM1及其辅因子RAN GTPase在有丝分裂开始中也起关键作用，因此HBX或HC核对CRM1失活也可能引起基因组不稳定性。我们的最初结果表明，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假设，即CRM1可能是病毒肝炎介导的致癌性的常见靶标，并为CRM1可能参与人类致癌作用提供了基础。