Tumor-derived fibronectin is involved in melanoma cell invasion and regulated by V600E B-Raf signaling pathway.
Melanomas are malignant tumors of melanocytes that, if not detected early, are highly aggressive and poorly treatable. Activation of extracellular signal-regulated (ERK)/mitogen-activated protein (MAP) kinase signaling is commonly found in melanomas mainly through oncogenic mutations of B-Raf. We previously reported that activation of ERK/MAP kinase stimulates synthesis of fibronectin by upregulating the transcription factor early growth response-1 (Egr-1). To further analyze the link between ERK/MAP kinase pathway and fibronectin in melanoma, we have studied the regulation and role of fibronectin produced by melanoma cells bearing oncogenic B-Raf mutation. We show that fibronectin is expressed in situ during tumor progression and that high fibronectin and Egr-1 levels are found in cells expressing this mutation. Expression of active mutants of B-Raf induces fibronectin, whereas endogenous fibronectin is inhibited by small interfering RNA (siRNA)-mediated depletion of B-Raf or Egr-1. In contrast, stimulation of ERK pathway is insufficient to promote fibronectin upregulation in normal melanocytes. Finally, we show that suppression of fibronectin by siRNA leads to decreased melanoma cell invasiveness in vitro. These results reveal a tumor-specific regulation of fibronectin by constitutive ERK/MAP kinase signaling and indicate that self-production of fibronectin may play a role in melanoma tumorigenesis, by promoting tumor cell invasion.
Gaggioli
Cédric
C
INSERM, U597, Biologie et Pathologies des Cellules Mélanocytaires, Faculté de Médecine, Nice Cédex 2, France.
Robert
Guillaume
G
Bertolotto
Corine
C
Bailet
Olivier
O
Abbe
Patricia
P
Spadafora
Anne
A
Bahadoran
Philippe
P
Ortonne
Jean-Paul
JP
Baron
Véronique
V
Ballotti
Robert
R
Tartare-Deckert
Sophie
S
D002478:Cells, Cultured; D018450:Disease Progression; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis / Q000378:metabolism*; D018698:Glutamic Acid; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D009154:Mutation; D009361:Neoplasm Invasiveness; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014633:Valine
D051766:Early Growth Response Protein 1; D005353:Fibronectins; D018698:Glutamic Acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D014633:Valine