Roles of microbiota-mediated hepatocarcinogenesis
微生物介导的肝癌发生的作用
基本信息
- 批准号:10702289
- 负责人:
- 金额:$ 25.47万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AdenovirusesAnimal ModelAntigen PresentationAntiviral ResponseAreaB-LymphocytesBinding ProteinsCell DeathCentrosomeChromosomal InstabilityChronicComplexDevelopmentDockingEtiologyGene ExpressionGenesGenomic InstabilityGoalsHepatitisHepatitis B VirusHepatitis CHepatitis C virusHepatitis Delta VirusHepatocarcinogenesisHepatocyteHomeostasisHumanImmunityInflammationInterferonsLinkLiverMediatingMitosisMitotic spindleMolecularMolecular ProfilingNatural regenerationNuclear ExportOncogenicPathogenesisPathway interactionsPatientsPilot ProjectsPlayPrimary carcinoma of the liver cellsProteinsResearchRoleSamplingSignal TransductionTissuesViral PhysiologyViral ProteinsViral hepatitisVirusVirus Diseasescarcinogenesischronic liver diseasemicrobiotanovelnucleocytoplasmic transportnucleophosminpreventran-binding protein 1toolvirus core
项目摘要
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.
我们以前的结果表明HBx包含一个功能性的核输出信号 利用Ran/Crm 1复合物的基序,Ran/Crm 1复合物是核质转运中必需的组分 许多细胞和病毒蛋白质。我们证明了HBx不仅使用而且破坏了 Ran/Crm 1依赖的活性,可能是为了防止宿主的抗病毒反应。这一发现 提示Ran/Crm 1复合物参与了B型肝炎病毒的分子发病机制。最近, 我们发现了Ran/Crm 1复合物在调节细胞蛋白质中的新作用, 中心体复制和有丝分裂纺锤体组装。我们发现核磷蛋白是一种新的 Ran/Crm 1负调节不必要的中心体复制的底物。此外,本发明还提供了一种方法, 我们证明了RanBP 1的B型肝炎病毒/ HBx依赖性激活, 已知使Ran/Crm 1复合物不稳定的蛋白质。RanBP 1也升高, 阳性肝组织和肝细胞癌。RanBP 1表达增加导致 多极纺锤体和异常有丝分裂。因此,B型肝炎病毒/ HBx导致染色体不稳定。这些发现使我们产生了一个新的假设 其中Ran/Crm 1复合物通过提供一个 控制细胞内稳态的装载码头机制,以及这种复合物的破坏 可能导致基因组不稳定,这可能是病毒性肝炎介导的 肝癌发生除了HBx,我们最近还完成了一项试点研究, 确定B淋巴细胞中丙型肝炎病毒核心相关基因表达谱。我们发现 丙型肝炎病毒核心可能通过选择性抑制参与免疫的基因来驱逐免疫。 抗原呈递这些研究有助于剖析病毒的活动, 在肝癌发生中必不可少。此外,我们还进行了分子分析研究, 比较腺病毒感染原代人肝细胞基因表达的变化 携带HBx或丙型肝炎病毒结构或非结构基因(p21 CORE、NS 3或NS 5A)。 我们还将这些基因表达谱与从丙型肝炎病毒中获得的基因表达谱进行了比较 - 来自慢性肝病患者和丙型肝炎病毒相关患者的感染肝脏样本 肝细胞癌我们发现丙型肝炎病毒相关蛋白在很大程度上诱导 与HBx相比,特别是,干扰素诱导基因27高度表达, 在丙型肝炎病毒或核心感染的肝细胞中表达, 慢性肝病或肝细胞癌,但在HBx中表达不显著 感染的肝细胞或B型肝炎病毒相关的慢性肝病或肝细胞 表明干扰素诱导基因27可能在丙型肝炎病毒中起作用 介导的肝细胞癌。总之,我们的研究结果表明,B型肝炎病毒 和丙型肝炎病毒主要通过不同途径促进肝细胞癌的发展 机制等
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Xin Wei Wang其他文献
Xin Wei Wang的其他文献
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{{ truncateString('Xin Wei Wang', 18)}}的其他基金
Molecular signatures for liver cancer diagnosis and treatment stratification
肝癌诊断和治疗分层的分子特征
- 批准号:
10262066 - 财政年份:
- 资助金额:
$ 25.47万 - 项目类别:
Viral exposure signatures may define individuals vulnerable for COVID-19
病毒暴露特征可能会定义个体是否容易感染 COVID-19
- 批准号:
10702767 - 财政年份:
- 资助金额:
$ 25.47万 - 项目类别:
Molecular signatures for liver cancer diagnosis and treatment stratification
肝癌诊断和治疗分层的分子特征
- 批准号:
10702334 - 财政年份:
- 资助金额:
$ 25.47万 - 项目类别:
The identification of human hepatocellular carcinoma metastasis genes
人肝癌转移基因的鉴定
- 批准号:
10926086 - 财政年份:
- 资助金额:
$ 25.47万 - 项目类别:
Mechanism of viral hepatitis-mediated hepatocarcinogenesis
病毒性肝炎介导的肝癌发生机制
- 批准号:
10262018 - 财政年份:
- 资助金额:
$ 25.47万 - 项目类别:
The identification of human hepatocellular carcinoma metastasis genes
人肝癌转移基因的鉴定
- 批准号:
10262174 - 财政年份:
- 资助金额:
$ 25.47万 - 项目类别:
The role of cancer stem cells in liver cancer heterogeneity and subtypes
癌症干细胞在肝癌异质性和亚型中的作用
- 批准号:
10262173 - 财政年份:
- 资助金额:
$ 25.47万 - 项目类别:
Identification of viral exposure signatures for early detection of liver cancer
鉴定病毒暴露特征以早期发现肝癌
- 批准号:
10703084 - 财政年份:
- 资助金额:
$ 25.47万 - 项目类别:
Viral exposure signatures may define individuals vulnerable for COVID-19
病毒暴露特征可能会定义个体是否容易感染 COVID-19
- 批准号:
10262566 - 财政年份:
- 资助金额:
$ 25.47万 - 项目类别:
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