Comprehensive analyses of Epstein-Barr virus(EBV) -dependent cellular gene expressions responsible for the viral oncogenesis

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The aim of this study was to identify the cellular genes closely related to or responsible for Epstein-Barr virus (EBV)-induced oncogenesis in naturally EBV-positive T/NK and epithelial tumor cells, by utilizing a unique molecule capable of eradicating EBV episomes from cells, i.e., dominant-negative EBNA1 (DNE1; Mol. Ther., 11(4):578-90, 2005). We prepared isogenic pairs of EBV-positive and-negative cell lines by DNE1 transduction and compared their malignant grade. Concomitantly alterations of cellular gene expression in those cell pairs were comprehensively assessed with the multi-cytokine assay and GeneChip microarray system, thereby elucidating the role(s) of EBV in malignant conversion. The results obtained are as follows.1. Adenovirus vector-mediated transduction of our DNE1 successfully eradicated EBV episomes from the majority of naturally EBV-positive T/NK lymphoma and epithelial tumor cell lines in a few days.2. The EBV-lost T/NK cells produced by DNE1 showed a striking suppression of their malignant phenotypes, such as prolongation of doubling time and loss of anchorage-independent growth potential, compared with parental EBV-harboring T/NK tumor cells. In a part of the EBV-lost T/NK cells, loss of viral genome also brought about cell death.3. The EBV-lost T/NK cells showed significantly decreased production of some cytokines, such as interleukin-9, compared with the parental EBV-harboring T/NK tumor cells. Conversely, the production levels of a few other cytokines were also found to be upregulated in the EBV-lost T/NK cells.These results indicate that the EBV-dependent malignant phenotypes in T/NK cells and perhaps also in epithelial cells, as in B-cell malignancy, are associated at least partly with upregulation (i.e., the autocrine mechanism) and/or downregulation of certain cytokine genes. We are planning to explore precisely the mechanisms of cytokine gene control and specific effects on EBV oncogenesis.