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.
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.
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