Linkage between STAT regulation and Epstein-Barr virus gene expression in tumors

Epstein-Barr virus (EBV) latency gene expression in lymphoblastoid cell lin es is regulated by EBNA2. However, the factors regulating viral expression in EBV-associated tumors that do not express EBNA2 are poorly understood. I n EBV-associated tumors, EBNA1 and frequently LMP1 are synthesized. We foun d that an alternative latent membrane protein 1 (LMP1) promoter, L1-TR, loc ated within the terminal repeats is active in both nasopharyngeal carcinoma and Hodgkin's disease tissues. Examination of the L1-TR and the standard E D-L1 LMP1 promoters in electrophoretic mobility shift assays revealed that both promoters contain functional STAT binding sites. Further, both LMP1 pr omoters responded in reporter assays to activation of JAK-STAT signaling. C otransfection of JAK1 or v-Src or treatment of cells with the cytokine inte rleukin-6 upregulated expression from ED-L1 and L1-TR reporter plasmids. Co transfection of a dominant negative STAT3 beta revealed that STAT3 is likel y to be the biologically relevant STAT for EBNA1 Qp and LMP1 L1-TR promoter regulation. In contrast, LMP1 expression from ED-L1 was not abrogated by S TAT3 beta, indicating that the two LMP1 promoters are regulated by differen t STAT family members. Taken together with the previous demonstration of JA K-STAT activation of Qp driven EBNA1 expression, this places two of the EBV genes most commonly expressed in tumors under the control of the same sign al transduction pathway. Immunohistochemical analyses of nasopharyngeal car cinoma tumors revealed that STAT3, STAT5, and STAT1 are constitutively acti vated in these tumors while STAT3 is constitutively activated in the malign ant cells of Hodgkin's disease. We hypothesize that chronic or aberrant STA T activation may be both a necessary and predisposing event for EBV-driven tumorigenesis in immunocompetent individuals.