Epstein-Barr virus (EBV)-associated, undifferentiated type of
nasopharyngeal carcinoma (NPC) is characterized by intensive leukocyte infiltration. Interaction between the infiltrating cells and the
tumor cells has been considered crucial for NPC development. Recruitment of the infiltrates can be directed by certain
chemokines present in the NPC tissues. It is unknown whether and how EBV lytic
infection regulates expression of the
chemokines. Using an antibody array, we first found that several
chemokines secreted from EBV-infected NPC cells are increased upon EBV reactivation into the lytic cycle, and
interleukin-8 (IL-8) is the
chemokine upregulated most significantly and consistently. Further studies showed that the EBV lytic
transactivator Zta is a potent inducer of
IL-8 in NPC cells, augmenting secreted and intracellular
IL-8 proteins, as well as
IL-8 RNA. Zta upregulates Egr-1, a cellular
transcription factor that has been involved in upregulation of
IL-8, but the Zta-induced
IL-8 expression is independent of Egr-1. The ability of Zta to transactivate the
IL-8 promoter is important for the induction of
IL-8, and we have identified two Zta-responsive elements in the promoter. Zta can bind to these two elements in vitro and can also be recruited to the
IL-8 promoter in vivo.
DNA-binding-defective Zta mutants can neither activate the
IL-8 promoter nor induce
IL-8 production. In addition, Zta-expressing NPC cells exert enhanced chemotactic activity that is mainly mediated by
IL-8. Since
IL-8 may contribute to not only leukocyte infiltration but also multiple oncogenic processes, the present study provides a potential link between EBV lytic
infection and pathogenesis of NPC.