Roles of microbiota-mediated hepatocarcinogenesis

微生物介导的肝癌发生的作用

• 批准号: 10702289
• 负责人: Xin Wei Wang
• 金额: $ 25.47万
• 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/10702289
• 关键词: Adenoviruses; Animal Model; Antigen Presentation; Antiviral Response; Area; B-Lymphocytes; Binding Proteins; Cell Death; Centrosome; Chromosomal Instability; Chronic; Complex; Development; Docking; Etiology; Gene Expression; Genes; Genomic Instability; Goals; Hepatitis; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatitis Delta Virus; Hepatocarcinogenesis; Hepatocyte; Homeostasis; Human; Immunity; Inflammation; Interferons; Link; Liver; Mediating; Mitosis; Mitotic spindle; Molecular; Molecular Profiling; Natural regeneration; Nuclear Export; Oncogenic; Pathogenesis; Pathway interactions; Patients; Pilot Projects; Play; Primary carcinoma of the liver cells; Proteins; Research; Role; Sampling; Signal Transduction; Tissues; Viral Physiology; Viral Proteins; Viral hepatitis; Virus; Virus Diseases; carcinogenesis; chronic liver disease; microbiota; novel; nucleocytoplasmic transport; nucleophosmin; prevent; ran-binding protein 1; tool; virus core

Our previous results indicate that HBx contains a functional nuclear export signal motif that utilizes the Ran/Crm1 complex, a component essential in nucleocytoplasmic transport of many cellular and viral proteins. We demonstrated that HBx not only uses but also disrupts Ran/Crm1-dependent activities, presumably to prevent a host antiviral response. This finding implicates the Ran/Crm1 complex in the molecular pathogenesis of hepatitis B virus. Recently, we uncovered a new role of the Ran/Crm1 complex in regulating cellular proteins that control centrosome duplication and mitotic spindle assembly. We revealed nucleophosmin as a novel substrate for Ran/Crm1 to negatively regulate unnecessary centrosome duplication. In addition, we demonstrated a hepatitis B virus / HBx -dependent activation of RanBP1, a Ran-binding protein that is known to destabilize the Ran/Crm1 complex. Elevated RanBP1 is also observed in positive liver tissues and in hepatocellular carcinoma. Increased expression of RanBP1 leads to multipolar spindles and abnormal mitoses. Thus, the combined effects of hepatitis B virus / HBx contribute to chromosome instability. These findings led us to generate a new hypothesis in which the Ran/Crm1 complex serves as the centrosome duplication checkpoint by providing a loading dock mechanism that controls cellular homeostasis, and the disruption of this complex may result in genomic instability, which may be an early step in viral hepatitis-mediated hepatocarcinogenesis. In addition to HBx, recently we have completed a pilot study by determining hepatitis C virus core-related gene expression profiles in B lymphocytes. We found that hepatitis C virus core may evict immunity by selectively suppressing genes involved in antigen presentation. These studies are useful in dissecting viral activities that are essential in hepatocarcinogenesis. Furthermore, we have conducted molecular profiling studies to compare the gene expression changes in primary human hepatocytes infected with adenoviruses harboring HBx or hepatitis C virus structural or non-structural genes (p21CORE, NS3 or NS5A). We also compared these gene expression profiles to those obtained from hepatitis C virus -infected liver samples from chronic liver disease patients and hepatitis C virus -related hepatocellular carcinoma. We found that hepatitis C virus -related proteins largely induce unique genes when compared to HBx. In particular, interferon-inducible gene 27 was highly expressed in hepatitis C virus or core infected hepatocytes and hepatitis C virus -related chronic liver disease or hepatocellular carcinoma, but was less significantly expressed in HBx infected hepatocytes or hepatitis B virus-related chronic liver disease or hepatocellular carcinoma, indicating that interferon-inducible gene 27 may play a role in hepatitis C virus -mediated hepatocellular carcinoma. In conclusion, our results suggest that hepatitis B virus and hepatitis C virus promote hepatocellular carcinoma development mainly through different mechanisms.

我们先前的结果表明，HBX包含一个功能性核输出信号基序，该基序利用了RAN/CRM1复合物，这是许多细胞和病毒蛋白的核质流中必不可少的成分。我们证明了HBX不仅使用，而且会破坏RAN/CRM1依赖性活动，这大概是为了防止宿主抗病毒药反应。这一发现暗示了RAN/CRM1复合物在乙型肝炎病毒的分子发病机理中。最近，我们发现了RAN/CRM1复合物在调节控制中心体重复和有丝分裂纺锤体组件的细胞蛋白中的新作用。我们揭示了核磷脂作为RAN/CRM1的新底物，以负调节不必要的中心体重复。此外，我们证明了乙型肝炎病毒 / HBX依赖性RANBP1的激活，RANBP1是一种RAN结合蛋白，已知可破坏RAN / CRM1复合物的稳定性。在阳性肝组织和肝细胞癌中也观察到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，丙型肝炎病毒 / HBX的综合作用导致染色体不稳定性。这些发现导致我们产生了一个新的假设，其中RAN/CRM1复合物通过提供控制细胞稳态的负载码头机制来充当中心体重复检查点，并且这种复合物的破坏可能导致基因组不稳定，这可能是病毒性肝炎肝炎介导的肝癌的早期步骤。除HBX外，最近我们还通过确定B淋巴细胞中与乙型肝炎病毒相关的基因表达谱进行了一项初步研究。我们发现，丙型肝炎病毒核心可能通过选择性抑制抗原表现的基因来驱逐免疫力。这些研究可用于解剖肝癌发生至关重要的病毒活性。此外，我们进行了分子分析研究，以比较感染具有HBX或丙型肝炎病毒结构或非结构基因的原代人肝细胞的基因表达变化（P21核，NS3或NS5A）。 我们还将这些基因表达谱与从肝炎病毒感染的肝病患者和丙型肝炎病毒相关的肝细胞癌肝癌中获得的基因表达谱。我们发现，与HBX相比，与丙型肝炎相关的蛋白很大程度上诱导了独特的基因。特别是，干扰素诱导的基因27在丙型肝炎病毒或核心感染的肝炎和丙型肝炎病毒相关的慢性肝病或肝细胞癌癌中高度表达干扰素诱导的基因27可能在肝炎病毒介导的肝细胞癌中起作用。总之，我们的结果表明，丙型肝炎病毒和丙型肝炎病毒主要通过不同的机制促进肝细胞癌发育。