O'Connell Michael P, Fiori Jennifer L, Kershner Emily K, Frank Brittany P, Indig Fred E, Taub Dennis D, Hoek Keith S, Weeraratna Ashani T
Laboratory of Immunology, Research Resources Branch, NIA, National Institutes of Health, Baltimore, Maryland 21224, USA.
J Biol Chem. 2009 Oct 16;284(42):28704-12. doi: 10.1074/jbc.M109.028498. Epub 2009 Aug 20.
Heparan sulfate proteoglycans (HSPGs) are important modulators for optimizing signal transduction of many pathways, including the Wnt pathways. We demonstrate that HSPG glycosaminoglycan levels increased with increasing metastatic potential of melanoma cells. Previous studies have demonstrated that Wnt5A increases the invasiveness of melanoma cells. We further demonstrate that HSPGs potentiate Wnt5A signaling, since enzymatic removal of the HSPG backbone resulted in a decrease in cellular Wnt5A levels, an increase in secreted Wnt5A in cell media, a decrease in downstream signaling, and ultimately, a decrease in invasiveness. Specifically, syndecan 1 and syndecan 4 expression correlated to Wnt5A expression and melanoma malignancy. Knockdown of syndecan 1 or 4 caused decreases in cell invasion, which could be restored by treating the cells with recombinant Wnt5A. These data indicate that syndecan 1 and 4 correlate to increased metastatic potential in melanoma patients and are an important component of the Wnt5A autocrine signaling loop, the activation of which leads to increased metastasis of melanoma.
硫酸乙酰肝素蛋白聚糖（HSPGs）是许多信号通路（包括Wnt信号通路）优化信号转导的重要调节因子。我们证明，随着黑色素瘤细胞转移潜能的增加，HSPG糖胺聚糖水平也会升高。先前的研究表明，Wnt5A可增加黑色素瘤细胞的侵袭性。我们进一步证明，HSPGs增强Wnt5A信号传导，因为酶促去除HSPG主链会导致细胞内Wnt5A水平降低、细胞培养基中分泌的Wnt5A增加、下游信号传导减少，最终导致侵袭性降低。具体而言，syndecan 1和syndecan 4的表达与Wnt5A表达及黑色素瘤恶性程度相关。敲低syndecan 1或4会导致细胞侵袭能力下降，而用重组Wnt5A处理细胞可恢复这种能力。这些数据表明，syndecan 1和4与黑色素瘤患者转移潜能增加相关，并且是Wnt5A自分泌信号环的重要组成部分，该信号环的激活会导致黑色素瘤转移增加。
