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: 8247164
• 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/8247164
• 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; response; tumorigenesis

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.

爱泼斯坦巴尔病毒（EBV）是一种致癌疱疹病毒，其密切参与许多免疫缺陷病毒。 人类的恶性肿瘤EBV相关肿瘤发生的遗传基础是EBV的协同作用 潜伏相关基因和不同的细胞遗传改变。仅免疫功能正常的个体 最小的EBV潜伏基因表达是可以容忍的，这是由于几种EBV编码的免疫原性。 潜伏基因产物然而，在艾滋病患者中，所有潜伏基因的表达（参考文献） 到III型潜伏期）有时是可以耐受的，这些基因的表达提供了许多必要的 肿瘤细胞发展的要素。在这种情况下，需要更少的细胞遗传改变来产生 恶性细胞群，这可能部分解释了艾滋病的易感性大大增加， EBV相关非霍奇金淋巴瘤的患者。 细胞microRNA，miR-155，是与癌症关系最密切的microRNA之一。miR-155是 由EB病毒III型潜伏期程序（但不是I型潜伏期程序）诱导，表明可能的作用 用于miR-155调节III型潜伏期信号转导。进一步的证据表明，miR-155信号是 与疱疹病毒生物学相关的研究由Rolf Renne的实验室和Bryan Cullen的实验室提供， 最近显示，卡波西肉瘤疱疹病毒（KSHV）编码miR-11的功能同源物， 155.最近两篇小鼠miR-155敲除论文表明miR-155对B细胞活化很重要 免疫攻击后的反应。我们假设，通过EB病毒III型潜伏期诱导miR-155表达， miR-155在促进EBV介导的B细胞活化中起作用，并且miR-155调节信号转导 导致艾滋病患者中EB病毒相关恶性肿瘤的途径。