Matrix metalloproteinase-9 (MMP-9) is involved in a wide range of normal and pathologic conditions, including inflammation, tissue repair, tumor invasion, and metastasis. Tumor necrosis factor alpha (TNFalpha) is a major proinflammatory cytokine that plays crucial roles in tumor progression, including tumor invasion and metastasis in the tumor microenvironment. Egr-1 is a member of the zinc-finger transcription factor family induced by diverse stimuli, including TNFalpha. However, the role of Egr-1 in MMP-9 expression was previously unknown. This study shows that Egr-1 directly binds to the MMP-9 promoter and plays an essential role for TNFalpha induction of MMP-9 transcription. Furthermore, Egr-1 together with NF-kappaB can synergistically activate both basal and TNFalpha-induced MMP-9 promoter activities in the presence of p300. We found that Egr-1 mediates extracellular signal-regulated kinase and c-jun NH(2)-terminal kinase mitogen-activated protein kinase-dependent MMP-9 transcription on TNFalpha stimulation. The requirement for Egr-1 in MMP-9 expression is further supported by the fact that HeLa cells expressing Egr-1 siRNA and Egr-1-null mouse embryonic fibroblasts were refractory to TNFalpha-induced MMP-9 expression. This report establishes that Egr-1 is essential for MMP-9 transcription in response to TNFalpha within the tumor microenvironment.
(c) 2010 AACR.