The role of cellular miRNA in Epstein-Barr virus oncogenesis

描述（由申请人提供）：普遍存在的疱疹病毒Epstein-Barr（EBV）与淋巴细胞癌和上皮癌相关，包括伯基特淋巴瘤、霍奇金淋巴瘤、移植后淋巴组织增生性疾病和鼻咽癌。潜伏膜蛋白1（LMP 1）在大多数EBV相关癌症中表达，已被鉴定为病毒的主要癌蛋白。已知LMP 1可以在体外转化啮齿动物成纤维细胞并在转基因小鼠中诱导肿瘤，并且这些事件需要通过LMP 1诱导的细胞信号传导途径的激活来启动转录。然而，参与LMP1肿瘤发生的特定细胞因子尚未明确定义。一类新的小的非编码调节RNA称为microRNA（miRNA）的异常表达已被证明有助于通过细胞过程，如增殖，分化和凋亡的失调致癌。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LMP 1存在下高度表达。先前的报道表明，miR-146 a在乳腺癌、胰腺癌、肺癌、甲状腺癌和前列腺癌组织中被诱导，表明该miRNA在肿瘤发生中可能起作用。我们推测miR-146a通过LMP1的诱导在EBV生物学中起作用，并且miR-146a可能参与LMP1介导的致癌信号传导。该提案将探索miR-146a在与LMP1介导的肿瘤发生和EBV生物学相关的信号通路中的作用。在第一个目标中，我们将通过用对照或miR146a抑制剂处理的LCL的mRNA阵列分析来研究miR146a在介导与LMP1信号传导和EBV生物学相关的途径中的作用。在目标2中，我们将评估miR146a在LMP 1赋予的抗凋亡中的作用，并评估miR146a从凋亡刺激中拯救细胞的能力。在目的3中，我们研究了miR146a在LMP1介导的侵袭性中的作用。最后，在目的4中，我们在小鼠模型中分析了miR146a在LMP1介导的转化和肿瘤发生中的作用。公共卫生相关性：EB病毒（EBV）与癌症有关，包括伯基特和霍奇金淋巴瘤和鼻咽癌。该提案探讨了称为miRNA的细胞调节基因在EBV相关肿瘤发生中的作用，该基因已被证明在非病毒性癌症中发挥作用。了解EBV导致癌症的过程将导致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.