HGF induces fibronectin matrix synthesis in melanoma cells through MAP kinase-dependent signaling pathway and induction of Egr-1.
The matrix fibronectin protein is a multifunctional adhesive molecule that promotes migration and invasiveness of many tumors including melanomas. Increased fibronectin synthesis has been associated with the metastatic potential of melanoma cells; however, the molecular mechanisms underlying fibronectin overexpression during melanoma development are poorly understood. We report that hepatocyte growth factor/scatter factor (HGF) induces fibronectin expression and its extracellular assembly on the surface of melanoma cells through activation of mitogen-activated protein (MAP) kinase pathway, and induction and transcriptional activation of Early growth response-1 (Egr-1). Inhibition of B-RAF/MAP kinase pathway by dominant-negative mutants and by U0126-abrogated HGF-induced Egr-1, and chromatin immunoprecipitation showed that Egr-1 is bound to the fibronectin promoter in response to HGF. Exogenously expressed Egr-1 increased fibronectin levels, while blockage of Egr-1 activation by expression of the Egr-1 corepressor NAB2 interfered with the upregulation of fibronectin synthesis induced by HGF, indicating that Egr-1 exerts a significant role in fibronectin expression in response to HGF. Finally, analysis of the expression pattern of fibronectin in melanoma cells demonstrated that fibronectin levels are correlated with constitutive MAP kinase signaling. Our data define a novel mechanism that might have important implications in regulation of melanoma progression by autocrine HGF signaling or by constitutive activation of MAP kinase pathway.
Gaggioli
Cédric
C
INSERM Unité 597, Biologie et Pathologies des Cellules Mélanocytaires, 'équipe labellisée la Ligue 2001', IFR 50, 06107 Nice Cédex 2, France.
Deckert
Marcel
M
Robert
Guillaume
G
Abbe
Patricia
P
Batoz
Michelle
M
Ehrengruber
Markus U
MU
Ortonne
Jean-Paul
JP
Ballotti
Robert
R
Tartare-Deckert
Sophie
S
D019898:Autocrine Communication / Q000502:physiology; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D051766:Early Growth Response Protein 1; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D005353:Fibronectins / Q000096:biosynthesis* / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000502:physiology; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics; D018631:ras Proteins / Q000502:physiology
D002070:Butadienes; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D005353:Fibronectins; D017874:Immediate-Early Proteins; D009570:Nitriles; D014157:Transcription Factors; C113580:U 0126; D017228:Hepatocyte Growth Factor; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins