Matrix metalloproteinase 9 Expression is induced by Epstein-Barr virus latent membrane protein 1 C-terminal activation regions 1 and 2

Nasopharyngeal carcinoma (NPC), which is closely associated with the Epstei n-Barr virus (EBV), is a highly metastatic malignant tumor. An important ac tivity in tumor invasion and metastasis is that of the 92-kDa type IV colla genase or gelatinase, matrix metalloproteinase 9 (MMP-9), which mediates th e degradation of the basement membrane and extracellular matrix. The expres sion of MMP-9 has been shown to be enhanced by the EBV oncoprotein, latent membrane protein 1 (LMP-1). LMP-1, which is expressed in NPC, has two essen tial signaling domains within the carboxy terminus, termed C-terminal activ ation regions 1 (CTAR-1) and CTAR-2, This study reveals that either signali ng domain can activate the MMP-9 promoter and induce MMP-9 activity; howeve r, LMP-1 deletion mutants lacking either CTAR-1 or CTAR-2 had a decreased a bility to induce MMP-9 expression. The deletion of both activation regions completely abolished the induction of MMP-9 activity, while the cotransfect ion of both the CTAR-1 and CTAR-2 deletion mutants restored MMP-9 activity to levels produced by wild-type LMP-1. The NF-kappa B and activator protein 1 (AP-1) binding sites in the MMP-9 promoter were essential for the activa tion of MMP-9 gene expression by both CTAR-1 and CTAR-2. The induction of M MP-9 expression by LMP-I and both CTAR-1 and CTAR-2 mutants was blocked by the overexpression of I kappa B. The tumor necrosis factor receptor-associa ted factor (TRAF) pathway also contributed to the activation of the MMP-9 p romoter as shown by the use of TRAF-2 and TRAF-3 dominant-negative construc ts. These data indicate that the activation of both the NF-KB and AP-1 path ways by LMP-1, CTAR-1, and CTAR-2 is necessary for the activation of MMP-9 expression. In NPC, LMP-1 may contribute to invasiveness and metastasis thr ough the induction of MMP-9 transcription and enzymatic activity.