Fibroblast growth factor-2 modulates melanoma adhesion and migration through a syndecan-4-dependent mechanism.
Fibroblast growth factor-2 (FGF-2), the most abundant growth factor produced by melanoma cells but not by normal melanocytes, is an important regulator of cell proliferation, migration and differentiation. In this study we show that M5 human metastatic melanoma cells' ability to migrate is significantly enhanced by exogenously added FGF-2 while, neutralization of endogenous FGF-2 stimulates their adhesion. Previously, we have demonstrated that FGF-2 distinctly modulates the synthesis of individual glycosaminoglycans/proteoglycans (GAGs/PGs) subclasses, changing both their amounts and distribution in M5 cells. Here, treatment with FGF-2 strongly reduces the expression levels of the heparan sulfate-containing proteoglycan, syndecan-4. Syndecan-4 is a focal adhesion component in a range of cell types, adherent to several different matrix molecules, including fibronectin (FN). The reduction in syndecan-4 expression by utilizing specific siRNA discriminately increased melanoma cell motility and decreased their attachment on FN, demonstrating a regulatory role of syndecan-4 on these cell functions. Syndecan-4 has previously been demonstrated to regulate focal adhesion kinase (FAK) phosphorylation. In this study FGF-2 was shown to downregulate FAK Y397-phosphorylation during FN-mediated M5 cell adhesion, promoting their migration. The observed decrease in FAK Y397 activation was correlated to syndecan-4 expression levels. Thus, a balance in syndecan-4 expression perpetrated by FGF-2 may be required for optimal M5 cell migration. These results suggest that essential in melanoma progression FGF-2, specifically regulates melanoma cell ability to migrate through a syndecan-4-dependent mechanism.
Chalkiadaki
Georgia
G
Department of Histology, Medical School, University of Crete, Heraklion, 71003, Greece.
Nikitovic
Dragana
D
Berdiaki
Aikaterini
A
Sifaki
Maria
M
Krasagakis
Kostantinos
K
Katonis
Pavlos
P
Karamanos
Nikos K
NK
Tzanakakis
George N
GN
D002448:Cell Adhesion / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002633:Chemotaxis; D018450:Disease Progression; D015536:Down-Regulation; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006026:Glycoside Hydrolases / Q000378:metabolism; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009362:Neoplasm Metastasis; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection
D005353:Fibronectins; D053671:Syndecan-4; D016222:Fibroblast Growth Factor 2; D006026:Glycoside Hydrolases