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

描述（由申请方提供）：爱泼斯坦巴尔病毒（EBV）是一种致癌疱疹病毒，与人类多种恶性肿瘤密切相关。EBV相关肿瘤发生的遗传基础是EBV潜伏相关基因和不同细胞遗传改变的协同作用。在免疫活性个体中，由于几种EBV编码的潜伏基因产物的免疫原性，仅可耐受最小的EBV潜伏基因表达。然而，在艾滋病患者中，有时可以耐受全部潜伏基因（称为III型潜伏期）的表达，并且这些基因的表达提供了肿瘤细胞发育的许多基本要素。在这种情况下，产生恶性细胞群所需的细胞遗传改变较少，这可能部分解释了艾滋病患者对EBV相关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由EBV III型潜伏期程序（但不是I型潜伏期程序）诱导，表明miR-155在调节III型潜伏期信号转导中的可能作用。Rolf Renne的实验室和Bryan Cullen的实验室提供了miR-155信号传导与疱疹病毒生物学相关的进一步证据，他们最近都表明卡波西肉瘤疱疹病毒（KSHV）编码miR- 155的功能同源物。最近两篇小鼠miR-155敲除论文表明，miR-155对于免疫攻击后的B细胞活化应答是重要的。我们假设，通过EBV III型潜伏期诱导miR-155在促进EBV介导的B细胞活化中起作用，并且miR-155调节导致AIDS患者中EBV相关恶性肿瘤的信号转导途径。公共卫生相关性：EB病毒与多种人类癌症有关，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多种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，它是由艾滋病相关恶性肿瘤中表达的EBV潜伏基因诱导的。

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.