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.