title: EGR-1 activation by EGF inhibits MMP-9 expression and lymphoma growth.
abstract: Progression of hematologic malignancies is strongly dependent on bidirectional interactions between tumor cells and stromal cells. Expression of members of the matrix metalloproteinase (MMP) family by stromal cells is a central event during these interactions. However, although several studies have focused on the mechanisms responsible for induction of MMP in stromal cells, the signals that negatively regulate their secretion of in these cells remain largely unknown. Here, we provide evidence that MMP-9 production by stromal cells is suppressed through activation of early growth response protein 1 (EGR-1), thereby inhibiting the growth of thymic lymphoma. We found that EGR-1 expression is induced in stromal cells after contact with lymphoma cells via epidermal growth factor (EGF). Moreover, development of thymic lymphoma was inhibited when induced by lymphoma cells overexpressing EGF compared with control lymphoma cells. Using transgenic mice containing MMP-9 promoter-driven luciferase transgene in its genome, we further demonstrated that EGF/EGR-1 repressed transcriptional activation of the MMP-9 gene by stromal cells. De novo expression of EGR-1 alone by gene transfer or exposure to recombinant human EGF also inhibited MMP-9 expression. Taken together, these results indicate that EGR-1 could be a source of novel targets for therapeutic intervention in lymphoid tumors in which MMP-9 plays a critical role.
authors.affiliation: Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, QC.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bouchard
authors.forename: Simon D
authors.initials: SD
authors.lastname: Bélanger
authors.forename: Katherine
authors.initials: K
authors.lastname: Biron-Pain
authors.forename: Yves
authors.initials: Y
authors.lastname: St-Pierre
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004790:Enzyme Induction / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005813:Genes, Synthetic; D006390:Hemangioendothelioma / Q000473:pathology; D006801:Humans; D016399:Lymphoma, T-Cell / Q000378:metabolism / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology; D013953:Thymus Neoplasms / Q000378:metabolism / Q000473:pathology*; D014158:Transcription, Genetic
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse