Epstein-Barr virus (EBV) infection has been closely associated with the development of nasopharyngeal carcinoma (NPC). How EBV interacts with epithelial cells to achieve transformation is poorly known. Although EBV latent membrane protein 1 (LMP-1) is the viral protein required for EBV transformation of resting B cells and proposed to be a critical player in NPC, the exact role of LMP-1 in the development of NPC is still uncertain. One of the genes regulated by LMP-1 is interferon (IFN) regulatory factor 7 (IRF-7). LMP-1 induces the expression of IRF-7, and activates IRF-7 protein by phosphorylation and nuclear translocation. However, little is known about the functions of the LMP-1 and IRF-7 interaction. We have found that IRF-7 has oncogenic potential and is expressed in human cancers, such as NPC. Also, LMP-1 and IRF-7 have a cooperative effect in transforming rodent cells. We hypothesize that IRF-7 is one of the mediators of LMP-l-induced transformation, and plays a role in the pathogenesis of EBV-associated tumors. The proposed experiments in the grant will address whether IRF-7 and in combination with LMP-1 plays a role in the pathogenesis of NPC.
In Aim 1, we will examine the possible linkage between IRF-7 and NPC. The expression and activation status of IRF-7 (i.e., nuclear IRF-7) will be compared between normal epithelial and NPC cells. Also, the relation between LMP-1 and IRF-7 in NPC will be examined with the use of immunostaining. The possible role of IRF-7 and LMP-1 in the development of NPC will be tested in Aim 2. We will make recombinant retroviruses carrying small interfering RNA (siRNA) for IRF-7 or LMP-1, and introduce the viruses to NPC cells, and monitor the development of tumors in nude mice. In addition, we will make the dominant mutant for LMP-1 transformation, and test if the dominant mutant could block the growth of NPC. The results from proposed experiments should shed light on the relation among LMP-1, IRF-7, and NPC. This study would lead to a better understanding of how LMP-1 and IRF-7 interact to participate in viral pathogenesis, latency, and transformation.
