Opposing effects of high- and low-molecular weight hyaluronan on CXCL12-induced CXCR4 signaling depend on CD44.
Opposing effects of high- and low-molecular weight hyaluronan on CXCL12-induced CXCR4 signaling depend on CD44.
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DOI：
10.1038/cddis.2013.364
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发表时间：
2013-10-03
影响因子：
9
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肿瘤微环境对癌症的发展和传播起着决定性的作用，例如，通过透明质酸（HA）等细胞外基质成分，以及通过调节肿瘤细胞行为和血管生成的趋化因子。在这里，我们报告了 HA、其受体 CD44 和趋化因子 CXCL12 在细胞运动和血管生成调节中的分子联系。研究发现，高分子量 HA (hHA) 可增强 HepG2iso 细胞和原代人脐静脉内皮细胞中 CXCL12 诱导的 CXCR4 信号传导，增强的 ERK 磷酸化和增加的细胞运动即可证明这一点。在多种检测中，CXCR4 信号传导的增强转化为血管萌芽和血管生成的增加。小 HA 寡糖 (sHA) 可有效抑制这些影响。 siRNA 介导的 CD44 表达减少和阻断 CD44 与 HA 相互作用的抗体都提供了证据，表明 CXCL12 诱导的 CXCR4 信号传导依赖于 hHA 与 CD44 的结合。一致地，发现 CD44 和 CXCR4 在 CXCL12 存在的情况下发生物理相互作用，这种相互作用可以被 sHA 抑制。这些发现为微环境成分如何与多成分复合物中的细胞表面受体相互作用以调节肿瘤生长和进展的关键方面提供了新的见解。
The tumor microenvironment makes a decisive contribution to the development and dissemination of cancer, for example, through extracellular matrix components such as hyaluronan (HA), and through chemokines that regulate tumor cell behavior and angiogenesis. Here we report a molecular link between HA, its receptor CD44 and the chemokine CXCL12 in the regulation of cell motility and angiogenesis. High-molecular-weight HA (hHA) was found to augment CXCL12-induced CXCR4 signaling in both HepG2iso cells and primary human umbilical vein endothelial cells, as evidenced by enhanced ERK phosphorylation and increased cell motility. The augmentation of CXCR4 signaling translated into increased vessel sprouting and angiogenesis in a variety of assays. Small HA oligosaccharides (sHA) efficiently inhibited these effects. Both siRNA-mediated reduction of CD44 expression and antibodies that block the interaction of CD44 with HA provided evidence that CXCL12-induced CXCR4 signaling depends on the binding of hHA to CD44. Consistently, CD44 and CXCR4 were found to physically interact in the presence of CXCL12, an interaction that could be inhibited by sHA. These findings provide novel insights into how microenvironmental components interact with cell surface receptors in multi-component complexes to regulate key aspects of tumor growth and progression.