The role of cellular miRNA in Epstein-Barr virus oncogenesis

描述(申请人提供)：无处不在的疱疹病毒Epstein-Barr(EBV)与淋巴细胞性和上皮性癌症有关，包括Burkitt淋巴瘤、霍奇金淋巴瘤、移植后淋巴增生性疾病和鼻咽癌。潜伏膜蛋白1(LMP1)在大多数EBV相关肿瘤中都有表达，已被确定为该病毒的主要癌蛋白。已知LMP1可以在体外转化啮齿动物成纤维细胞，并在转基因小鼠体内诱发肿瘤，这些事件需要通过LMP1诱导的细胞信号通路的激活来启动转录。然而，参与LMP1肿瘤发生的特定细胞因子还没有明确的定义。一类新的被称为microRNAs(MiRNAs)的新的非编码小RNA的异常表达被证明通过对细胞增殖、分化和凋亡等过程的失调而促进癌症的发生。我们已经证明LMP1可以改变细胞miRNA的表达。特别是一种miRNA，miR-146a，在LMP1存在下高度表达。以前的报道表明miR-146a在乳腺癌、胰腺癌、肺癌、甲状腺和前列腺癌组织中被诱导，这表明该miRNA在肿瘤发生中可能发挥作用。我们推测LMP1诱导miR-146a在EB病毒生物学中发挥作用，miR-146a可能参与LMP1介导的致癌信号。该提案将探索miR-146a在LMP1介导的肿瘤发生和EBV生物学相关信号通路中的作用。在第一个目标中，我们将通过对对照或miR146a抑制剂处理的LCL的mRNA阵列分析，研究miR146a在与LMP1信号转导和EBV生物学相关的通路中的作用。在目标2中，我们将评估miR146a在LMP1诱导的抗凋亡中的作用，并评估miR146a从凋亡刺激中拯救细胞的能力。在目标3中，我们研究了miR146a在LMP1介导的侵袭中的作用。最后，在目标4中，我们分析了miR146a在LMP1介导的转化和小鼠肿瘤发生中的作用。公共卫生相关性：EB病毒(EBV)与癌症有关，包括Burkitt‘s和Hodgkin’s淋巴瘤以及鼻咽癌。这项提案探索了被称为miRNA的细胞调控基因在EBV相关肿瘤发生中的作用，这些基因已被证明在非病毒性癌症中发挥作用。对EBV致癌过程的了解将导致EBV相关疾病的新疗法。

DESCRIPTION (provided by applicant): The ubiquitous herpes virus Epstein-Barr (EBV) is associated with lymphocytic and epithelial cancers, including Burkitt's lymphoma, Hodgkin's lymphoma, post-transplant lymphoproliferative disease, and nasopharyngeal carcinoma. The latent membrane protein 1 (LMP1), which is expressed in most EBV associated cancers, has been identified as the major oncoprotein of the virus. It is known that LMP1 can transform rodent fibroblasts in vitro and induce tumors in transgenic mice, and these events require initiation of transcription by LMP1 induced activation of cell signaling pathways. However, the specific cellular factors involved in LMP1 oncogenesis have not been clearly defined. Aberrant expression of a novel class of small noncoding regulatory RNAs known as microRNAs (miRNAs) have been shown to contribute to carcinogenesis through dysregulation of cell processes such as proliferation, differentiation, and apoptosis. We have demonstrated that LMP1 can alter the expression of cellular miRNA. One miRNA in particular, miR-146a, is highly expressed in the presence of LMP1. Previous reports have indicated that miR-146a is induced in cancers of the breast, pancreas, lung, thyroid and prostate tissues, suggesting a possible role for this miRNA in oncogenesis. We hypothesize that the induction of miR-146a by LMP1 plays a role in EBV biology and that miR-146a may be involved in LMP1 mediated oncogenic signaling. This proposal will explore the role of miR-146a in signaling pathways pertaining to LMP1 mediated oncogenesis and EBV biology. In the first aim, we will examine the role of miR146a in mediating pathways pertinent to LMP1 signaling and EBV biology, through mRNA array analysis of LCLs treated with control or miR146a inhibitors. In Aim 2, we will evaluate the role of miR146a in the resistance to apoptosis conferred by LMP1, and assess the ability of miR146a to rescue cells from apoptotic stimuli. In Aim 3, we examine the role of miR146a in LMP1-mediated invasiveness. Finally, in Aim 4, we analyze the role of miR146a in LMP1-mediated transformation and tumorigenesis in a mouse model. PUBLIC HEALTH RELEVANCE: Epstein-Barr virus (EBV) is associated with cancers, including Burkitt's and Hodgkin's lymphomas and nasopharyngeal carcinoma. This proposal explores the role of cellular regulatory genes known as miRNA, which have been shown to play a role in non-viral cancers, in EBV-related oncogenesis. An understanding of the process by which EBV causes cancer will lead to novel treatments for EBV-related diseases.