Abstract
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.
Highlights
Tumor metastasis is a complex multistep process that involves tumor growth, migration, cell adhesion, and invasion
We found that Egr-1 mediates extracellular signal– regulated kinase (ERK)– and c-jun NH2-terminal kinase (JNK)–dependent, but not p38 mitogen-activated protein kinase (MAPK)–dependent, Matrix metalloproteinase-9 (MMP-9) transcription in response to Tumor necrosis factor α (TNFα) stimulation
To determine the transcriptional activity of Matrix metalloproteinases (MMP)-9 gene promoter by TNFα, we isolated the 5′-regulatory region of the human MMP-9 gene located within 925 bp upstream of the transcriptional start site and subcloned it into the pGL3-Luc luciferase reporter vector, yielding pMMP9Luc(−925/+13)
Summary
Tumor metastasis is a complex multistep process that involves tumor growth, migration, cell adhesion, and invasion. Proteolytic degradation of the extracellular matrix and basement membranes is a crucial event in tumor invasion, metastasis, and angiogenesis [1]. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases that are capable of degrading extracellular matrix proteins and are involved in a wide range of normal and pathologic conditions, including inflammation, tissue repair, tumor invasion, and metastasis [1, 2]. MMP-9 is of particular interest because its basal expression is normally low in most cells, whereas it is highly expressed in most human cancers in response to diverse growth factors and cytokines. Upregulation of MMP-9 expression contributes to the development of tumor progression, including angiogenesis [4, 5], invasion, and metastasis [6,7,8]
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