The Epstein-Barr virus induced tumor suppressor miR-34a is growth promoting in EBV-infected B cells

Epstein-Barr virus (EBV) infection of primary human B cells drives their indefinite proliferation into lymphoblastoid cell lines (LCLs). B cell immortalization depends on expression of viral latency genes as well as the regulation of host genes. Given the important role of miRNAs in regulating fundamental cellular processes, in this study we assayed changes in host miRNA expression during primary B cell infection by EBV. We observed and validated dynamic changes in several miRNAs from early proliferation through immortalization; oncogenic miRNAs were induced and tumor suppressor miRNAs were largely repressed. However, one miRNA described as a p53-targeted tumor suppressor, miR-34a, was strongly induced by EBV infection and expressed in many EBV and KSHV-infected lymphoma cell lines. The EBV latent membrane protein 1 (LMP1) was sufficient to induce miR-34a requiring downstream NFκB activation, but independent of functional p53. Furthermore, over-expression of miR-34a was not toxic in several B lymphoma cell lines and inhibition of miR-34a impaired the growth of EBV transformed cells. This study identifies a pro-growth role for a tumor suppressive miRNA in oncogenic virus-mediated transformation highlighting the importance of studying miRNA function in different cellular contexts. miRNA expression profiling of human B-cells, EBV-infected, proliferating B cells and Monoclonal LCLs from 3 different donors was conducted with the use of up to 2 μg total RNA for sample