The role of cellular miRNA in Epstein-Barr virus oncogenesis

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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.