Roles of microbiota-mediated hepatocarcinogenesis

微生物介导的肝癌发生的作用

• 批准号: 10925957
• 负责人: Xin Wei Wang
• 金额: $ 57.3万
• 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/10925957
• 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; Running; 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.

我们之前的研究结果表明，HBx含有一个功能性核输出信号基元，该基元利用Ran/Crm1复合物，这是许多细胞和病毒蛋白的核胞质运输所必需的成分。我们证明HBx不仅使用而且破坏Ran/ crm1依赖的活性，可能是为了阻止宿主的抗病毒反应。这一发现暗示Ran/Crm1复合体参与了乙型肝炎病毒的分子发病机制。最近，我们发现了Ran/Crm1复合体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。我们发现核蛋白是Ran/Crm1负性调节不必要的中心体复制的新底物。此外，我们证明了乙型肝炎病毒/ HBx依赖性的RanBP1激活，RanBP1是一种已知的破坏Ran/Crm1复合物稳定的Ran结合蛋白。在阳性肝组织和肝细胞癌中也观察到RanBP1升高。RanBP1表达增加导致多极纺锤体和有丝分裂异常。因此，乙型肝炎病毒/ 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/Crm1复合体通过提供控制细胞稳态的装载码头机制作为中心体重复检查点，并且该复合体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抗原呈递的基因来驱逐免疫。这些研究有助于解剖在肝癌发生过程中必不可少的病毒活动。此外，我们还进行了分子谱研究，比较了携带HBx或丙型肝炎病毒结构或非结构基因（p21CORE、NS3或NS5A）的腺病毒感染的原代人肝细胞的基因表达变化。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的肝细胞癌中获得的丙型肝炎病毒感染的肝脏样本进行了比较。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。特别是，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表达，而在HBx感染的肝细胞或乙型肝炎病毒相关的慢性肝病或肝细胞癌中低表达，提示干扰素诱导基因27可能在丙型肝炎病毒介导的肝细胞癌中发挥作用。总之，我们的研究结果表明，乙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

Cell cycle-dependent phosphorylation of nucleophosmin and its potential regulation by peptidyl-prolyl cis/trans isomerase.

核磷蛋白的细胞周期依赖性磷酸化及其通过肽基脯氨酰顺/反异构酶的潜在调节。

• 发表时间: 2015
• 期刊: Journal of molecular biochemistry
• 作者: Zhao,Xuelian;Ji,Junfang;Yu,Li-Rong;Veenstra,Timothy;Wang,XinWei
• 通讯作者: Wang,XinWei

The repertoire of CSF antiviral antibodies in patients with neuroinflammatory diseases.

• DOI: 10.1126/sciadv.abq6978
• 发表时间: 2023-01-04
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Enose-Akahata, Yoshimi;Wang, Limin;Almsned, Fahad;Johnson, Kory R.;Mina, Yair;Ohayon, Joan;Wang, Xin Wei;Jacobson, Steven
• 通讯作者: Jacobson, Steven

Let-7g targets collagen type I alpha2 and inhibits cell migration in hepatocellular carcinoma.

• DOI: 10.1016/j.jhep.2009.12.025
• 发表时间: 2010-05
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: Ji J;Zhao L;Budhu A;Forgues M;Jia HL;Qin LX;Ye QH;Yu J;Shi X;Tang ZY;Wang XW
• 通讯作者: Wang XW

Current concepts of immune based treatments for patients with HCC: from basic science to novel treatment approaches.

• DOI: 10.1136/gutjnl-2014-307990
• 发表时间: 2015-05
• 期刊: Gut
• 影响因子: 24.5
• 作者: Greten TF;Wang XW;Korangy F
• 通讯作者: Korangy F

Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma.

• DOI: 10.1016/j.ccell.2017.05.009
• 发表时间: 2017-07-10
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Chaisaingmongkol J;Budhu A;Dang H;Rabibhadana S;Pupacdi B;Kwon SM;Forgues M;Pomyen Y;Bhudhisawasdi V;Lertprasertsuke N;Chotirosniramit A;Pairojkul C;Auewarakul CU;Sricharunrat T;Phornphutkul K;Sangrajrang S;Cam M;He P;Hewitt SM;Ylaya K;Wu X;Andersen JB;Thorgeirsson SS;Waterfall JJ;Zhu YJ;Walling J;Stevenson HS;Edelman D;Meltzer PS;Loffredo CA;Hama N;Shibata T;Wiltrout RH;Harris CC;Mahidol C;Ruchirawat M;Wang XW;TIGER-LC Consortium
• 通讯作者: TIGER-LC Consortium