Mechanism of viral hepatitis-mediated hepatocarcinogenesis

病毒性肝炎介导的肝癌发生机制

基本信息

  • 批准号:
    10262018
  • 负责人:
  • 金额:
    $ 17.29万
  • 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:
  • 项目状态:
    未结题

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.
我们以前的研究结果表明,HBx包含一个功能性的核输出信号基序,利用Ran/Crm 1复合物,许多细胞和病毒蛋白质的核质运输中必不可少的组成部分。我们证明,HBx不仅使用,而且破坏Ran/Crm 1依赖的活动,大概是为了防止宿主的抗病毒反应。这一发现表明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复合物在调节控制中心体复制和有丝分裂纺锤体组装的细胞蛋白中的新作用。我们揭示了核磷蛋白作为一种新的底物Ran/Crm 1负调控不必要的中心体复制。此外,我们证明了RanBP 1的B型肝炎病毒/ HBx依赖性激活,RanBP 1是一种已知使Ran/Crm 1复合物不稳定的Ran结合蛋白。在阳性肝组织和肝细胞癌中也观察到RanBP 1升高。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的联合作用导致染色体不稳定。这些发现使我们产生了一个新的假设,其中Ran/Crm 1复合物作为中心体复制检查点,通过提供控制细胞内稳态的装载码头机制,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的早期步骤。除HBx外,最近我们还完成了一项初步研究,确定了B淋巴细胞中丙型肝炎病毒核心相关基因的表达谱。我们发现丙型肝炎病毒核心可能通过选择性抑制抗原呈递相关基因而驱逐免疫力。这些研究有助于剖析肝癌发生过程中必不可少的病毒活动。此外,我们进行了分子谱研究,以比较携带HBx或丙型肝炎病毒结构或非结构基因(p21 CORE,NS 3或NS 5A)的腺病毒感染的原代人肝细胞中的基因表达变化。我们还将这些基因表达谱与从慢性肝病患者和丙型肝炎病毒相关肝细胞癌的丙型肝炎病毒感染的肝脏样本中获得的基因表达谱进行了比较。我们发现,与HBx相比,丙型肝炎病毒相关蛋白在很大程度上诱导了独特的基因.特别地,干扰素诱导基因27在丙型肝炎病毒或核心感染的肝细胞和丙型肝炎病毒相关的慢性肝病或肝细胞癌中高度表达,但在HBx感染的肝细胞或B病毒相关的慢性肝病或肝细胞癌中表达不太显著,表明干扰素诱导基因27可能在丙型肝炎病毒介导的肝细胞癌中起作用。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的机制促进肝细胞癌的发展。

项目成果

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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:
    $ 17.29万
  • 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:
    $ 17.29万
  • 项目类别:
Roles of microbiota-mediated hepatocarcinogenesis
微生物介导的肝癌发生的作用
  • 批准号:
    10925957
  • 财政年份:
  • 资助金额:
    $ 17.29万
  • 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:
    $ 17.29万
  • 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:
    $ 17.29万
  • 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:
    $ 17.29万
  • 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:
    $ 17.29万
  • 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:
    $ 17.29万
  • 项目类别:
Roles of microbiota-mediated hepatocarcinogenesis
微生物介导的肝癌发生的作用
  • 批准号:
    10702289
  • 财政年份:
  • 资助金额:
    $ 17.29万
  • 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:
    $ 17.29万
  • 项目类别:

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