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Yoshizaki, T. et al.

Yoshizaki, Sato, Murono, Pagano, Furukawa,

Matrix metalloproteinase 9 is induced by the Epstein-Barr virus BZLF1 transactivator.

Type IV collagenases, matrix metalloproteinase (MMP) 2 and MMP9 are implicated in tumor invasion and metastasis. In patients with nasopharyngeal carcinoma ( NPC), poor prognosis due to development of local and distant metastasis has been reported to be predicted by antibody titers against the Z protein which is an AP-1 family transcription factor encoded by the EBV BZLF1 immediate-early gene. Here we report that in patients with NPC, expression of Z in tumor cells correlates with advanced cervical lymph node metastasis which may suggest that Z affects tumor invasion and metastasis. We therefore tested if Z would induce expression of type IV collagenases. Transfection of Z expression plasmid into the C33A epithelial cell line increased expression of MMP9, but MMP2 expression was unaltered. Mutational analysis of the Z protein revealed that, in addition to all three functional domains of Z (dimerization domain, DNA binding domain, and activation domain), the carboxyl terminal 17 amino acids which stabilize the Z protein were necessary for induction of MMP9 expression. Analysis of the MMP9 promoter demonstrated that only AP-1 site close to the transcriptional start-site was essential for transactivation by Z. Previously we reported that Epstein-Barr virus latent membrane protein 1 (LMP1) stimulates MMP9 expression (Yoshizaki et al. Proc. Natl. Acad. Sci. 1998; 95: 3621-6). Thus, Z together with LMP1 may contribute to invasion and metastasis of NPC by inducing expression of MMP9.[1]

References

Matrix metalloproteinase 9 is induced by the Epstein-Barr virus BZLF1 transactivator. Yoshizaki, T., Sato, H., Murono, S., Pagano, J.S., Furukawa, M. Clin. Exp. Metastasis (1999) [Pubmed]

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