Role of the cellular microRNA, miR-155, in EBV type III latency signaling

细胞 microRNA miR-155 在 EBV III 型潜伏信号传导中的作用

• 批准号: 8060608
• 负责人: ERIK K FLEMINGTON
• 金额: $ 29.99万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060608
• 关键词: Acquired Immunodeficiency Syndrome; Address; Apoptosis; B-Cell Activation; B-Cell Lymphomas; Biology; Burkitt Lymphoma; Cells; Cloning; Data Analyses; Development; Elements; Epstein-Barr Virus latency; Gene Expression; Gene Targeting; Genes; Genetic; Growth; Herpesviridae; Hodgkin Disease; Homologous Gene; Human; Human Herpesvirus 4; Immune; Individual; Kaposi Sarcoma; Knock-out; Malignant Neoplasms; Mediating; MicroRNAs; Mus; Mutation; Nasopharynx Carcinoma; Non-Hodgkin' s Lymphoma; Oncogenic; Paper; Patients; Play; Population; Predisposition; Probability; Proteins; Reagent; Role; Signal Transduction; Signal Transduction Pathway; Transforming Growth Factor beta; Untranslated Regions; Validation; base; cancer cell; inhibitor/antagonist; neoplastic cell; programs; public health relevance; response; tumorigenesis

DESCRIPTION (provided by applicant): The Epstein Barr virus (EBV) is an oncogenic herpesvirus that is intimately involved in a number of malignancies in humans. The genetic basis of EBV associated oncogenesis is the concerted action of EBV latency associated genes and varying cellular genetic alterations. In immuno-competent individuals only minimal EBV latency gene expression can be tolerated due to the immunogeneticity of several EBV encoded latency gene products. In AIDS patients, however, expression of the full repertoire of latency genes (referred to as type III latency) can sometimes be tolerated and expression of these genes provide many essential elements of tumor cell development. In this setting, fewer cellular genetic alterations are required to give rise to malignant cell populations and this probably partly explains the greatly increased susceptibility of AIDS patients to EBV associated non-Hodgkin's lymphomas. The cellular microRNA, miR-155, is one of the most highly implicated microRNAs in cancer. miR-155 is induced by the EBV type III latency program (but not the type I latency program) suggesting a possible role for miR-155 in modulating type III latency signal transduction. Further evidence that miR-155 signaling is relevant to herpesvirus biology has been provided by Rolf Renne's lab and by Bryan Cullen's lab who both showed recently that the Kaposi's Sarcoma Herpes virus (KSHV) encodes a functional homologue of miR- 155. Two mouse miR-155 knock out papers recently showed that miR-155 is important for B cell activation responses following immune challenge. We hypothesize that induction of miR-155 by EBV type III latency plays a role in facilitating EBV mediated B cell activation and that miR-155 modulates signal transduction pathways that contribute to EBV associated maligancies in AIDS patients. PUBLIC HEALTH RELEVANCE: EBV is associated with a number of human cancers including nasopharyngeal carcinoma, Hodgkin's lymphoma, Burkitt's lymphoma as well as a number of B-cell lymphomas in AIDS patients. Our studies are aimed at addressing the role of an oncogenic cellular microRNA, miR-155, that is induced by EBV latency genes expressed in AIDS associated malignancies.

描述(申请人提供)：爱泼斯坦-巴尔病毒(EBV)是一种致癌性疱疹病毒，与人类的许多恶性肿瘤密切相关。EBV相关肿瘤发生的遗传学基础是EBV潜伏期相关基因和不同细胞遗传学改变的协同作用。在有免疫能力的个体中，由于几种EBV编码的潜伏期基因产物的免疫遗传性，只能耐受最低限度的EBV潜伏期基因表达。然而，在艾滋病患者中，所有潜伏期基因的表达(称为III型潜伏期)有时是可以容忍的，这些基因的表达提供了许多肿瘤细胞发育的基本要素。在这种情况下，需要较少的细胞遗传改变才能引起恶性细胞群，这可能部分解释了艾滋病患者对EBV相关的非霍奇金淋巴瘤的易感性大大增加。细胞microRNA miR-155是与癌症关系最密切的microRNA之一。MiR-155是由EBV III型潜伏期程序(而不是I型潜伏期程序)诱导的，这表明miR-155可能在调制III型潜伏期信号转导中发挥作用。Rolf Renne的实验室和Bryan Cullen的实验室提供了miR-155信号与疱疹病毒生物学相关的进一步证据，他们最近都表明Kaposi的肉瘤疱疹病毒(KSHV)编码miR-155的功能同源物。最近发表的两篇小鼠miR-155基因敲除论文表明，miR-155在免疫攻击后的B细胞激活反应中起重要作用。我们假设，EBV III型潜伏期诱导miR-155在促进EBV介导的B细胞激活中发挥作用，并且miR-155调节信号转导通路，从而促进艾滋病患者EBV相关性恶性疾病的发生。公共卫生相关性：EB病毒与许多人类癌症有关，包括鼻咽癌、霍奇金淋巴瘤、伯基特淋巴瘤以及艾滋病患者的一些B细胞淋巴瘤。我们的研究旨在解决致癌细胞microRNA miR-155的作用，它是由在艾滋病相关恶性肿瘤中表达的EBV潜伏基因诱导的。