EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines
EGF receptor modifies cellular responses to hyaluronan in glioblastoma cell lines
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DOI：
10.1054/jocn.2001.1063
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发表时间：
2002-05-01
影响因子：
2
通讯作者：
Novak, U
中科院分区：
文献类型：
--
作者：
Tsatas, D;Kanagasundaram, V;Novak, U
细胞与细胞外基质成分透明质酸的接触在神经胶质瘤细胞侵袭和增殖中起着关键作用。尽管神经胶质瘤细胞可以通过 CD44 的表达将透明质酸结合到其表面，但配体-受体相互作用后的细胞反应仍知之甚少。鉴于大部分人类高级神经胶质瘤过度表达表皮生长因子受体 (EGFR) 和 ErbB2，本研究旨在调查 CD44 与这些受体酪氨酸激酶之间是否存在相互作用。在这里，我们提供了 CD44 在神经胶质瘤细胞系 U87MG 和 SMA560 中与 EGFR 和 ErbB2 共免疫沉淀的证据。透明质酸治疗介导细胞外信号调节激酶的快速和瞬时磷酸化；神经胶质瘤细胞系中的 1 和 2（ERK1 和 ERK2）。 EGFR 的共表达增强了这种对透明质酸的反应。 EGFR 还差异性地修饰了透明质酸诱导的许多与细胞侵袭和增殖相关的基因的表达。 Northern印迹分析表明，编码尿激酶型纤溶酶原激活剂（uPA）、尿激酶型纤溶酶原激活剂受体（uPAR）、纤溶酶原激活剂抑制剂-1（PAI-1）、金属蛋白酶组织抑制剂（TIMP-1）和c-myc的基因响应透明质酸而上调。此外，酶谱分析显示透明质酸刺激细胞的条件培养基中uPA水平增加。这些结果表明胶质瘤细胞系中 CD44 和 EGFR 之间存在新的功能关系。 CD44 与受体酪氨酸激酶形成稳定复合物的能力可能为调节细胞侵袭和增殖提供通用系统，使透明质酸能够激活信号转导途径并通过 EGFR 依赖性方式调节基因表达。这些发现为透明质酸调节恶性表型的模式提供了新的见解，并表明 EGFR-CD44 相互作用在神经胶质肿瘤发生中的作用。 (C) 2002 年，爱思唯尔科学有限公司出版。
Cell contact with the extracellular matrix component, hyaluronan, plays a pivotal role in glioma cell invasion and proliferation. Although it is well established that glioma cells can bind hyaluronan to their surface via the expression of CD44, the cellular responses following ligand-receptor interaction remain poorly understood. Given that a large proportion of human high grade gliomas over express the epidermal growth factor receptor (EGFR) and ErbB2, this study aimed to investigate whether an interaction exists between CD44 and these receptor tyrosine kinases. Here we present evidence that CD44 co-immunoprecipitates with EGFR and ErbB2 in the glioma cell lines U87MG and SMA560. Hyaluronan treatment mediated the rapid and transient phosphorylation of extracellular signal regulated kinases; 1 and 2 (ERK1 and ERK2) in glioma cell lines. This response to hyaluronan was augmented by the co-expression of EGFR. EGFR also differentially modified the hyaluronan induced expression of a number of genes associated with cellular invasion and proliferation. Northern blot analysis demonstrated that genes encoding urokinase type plasminogen activator (uPA), urokinase type plasminogen activator receptor (uPAR), plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinases (TIMP-1) and c-myc were up-regulated in response to hyaluronan. Furthermore, zymographic analysis revealed increased levels of uPA in the conditioned medium of hyaluronan stimulated cells. These results indicate a novel functional relationship between CD44 and EGFR in glioma cell lines. The capacity of CD44 to form stable complexes with receptor tyrosine kinases may provide a versatile system for the regulation of cellular invasion and proliferation that allows hyaluronan to activate signal transduction pathways and modulate gene expression via an EGFR-dependent manner. These findings provide new insights into the mode by which hyaluronan regulates the malignant phenotype and also suggest a role for EGFR-CD44 interactions in glial tumorigenesis. (C) 2002 Published by Elsevier Science Ltd.