Fibroblast growth factor-2 modulates melanoma adhesion and migration through a syndecan-4-dependent mechanism
Fibroblast growth factor-2 modulates melanoma adhesion and migration through a syndecan-4-dependent mechanism
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DOI：
10.1016/j.biocel.2008.11.008
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发表时间：
2009-06-01
影响因子：
4
通讯作者：
Tzanakakis, George N.
中科院分区：
文献类型：
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作者：
Chalkiadaki, Georgia;Nikitovic, Dragana;Tzanakakis, George N.
成纤维细胞生长因子-2（FGF-2）是黑色素瘤细胞产生的最丰富的生长因子，但不是由正常黑色素细胞产生的，是细胞增殖、迁移和分化的重要调节因子。在这项研究中，我们表明，M5人转移性黑色素瘤细胞的迁移能力显着增强外源性加入FGF-2，而内源性FGF-2的中和刺激其粘附。以前，我们已经证明，FGF-2明显调节个别糖胺聚糖/蛋白聚糖（GAG/PG）亚类的合成，改变它们在M5细胞中的数量和分布。在这里，用FGF-2治疗强烈降低了含硫酸乙酰肝素的蛋白聚糖多配体蛋白聚糖-4的表达水平。多配体蛋白聚糖-4是一系列细胞类型中的粘着斑组分，粘附于几种不同的基质分子，包括纤连蛋白（FN）。通过利用特异性siRNA减少多配体蛋白聚糖-4的表达有区别地增加了黑素瘤细胞的运动性并减少了它们在FN上的附着，证明了多配体蛋白聚糖-4对这些细胞功能的调节作用。Syndecan-4先前已被证明调节粘着斑激酶（FAK）磷酸化。在这项研究中，FGF-2被证明在FN介导的M5细胞粘附过程中下调FAK Y397磷酸化，促进其迁移。所观察到的FAK Y397活化的降低与多配体蛋白聚糖-4表达水平相关。因此，平衡syndecan-4的表达所犯的FGF-2可能需要最佳的M5细胞migration.These结果表明，在黑色素瘤的进展FGF-2，特别是调节黑色素瘤细胞的能力，通过syndecan-4依赖的机制迁移。(C)2008爱思唯尔有限公司保留所有权利。
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. (C) 2008 Elsevier Ltd. All rights reserved.