Differential Gene Expression Analysis Reveals Activation of Growth Promoting Signaling Pathways by Tenascin-C
Differential Gene Expression Analysis Reveals Activation of Growth Promoting Signaling Pathways by Tenascin-C
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DOI：
10.1158/0008-5472.can-04-1234
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发表时间：
2004-10
期刊：
影响因子：
11.2
通讯作者：
C. Ruiz;Wen-xiu Huang;M. Hegi;K. Lange;M. Hamou;E. Fluri;E. Oakeley;R. Chiquet‐Ehrismann;
中科院分区：
文献类型：
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作者：
C. Ruiz;Wen-xiu Huang;M. Hegi;K. Lange;M. Hamou;E. Fluri;E. Oakeley;R. Chiquet‐Ehrismann;
Tenascin-C 是一种粘附调节细胞外基质分子，在肿瘤基质中高表达并刺激肿瘤细胞增殖。 Tenascin-C 抑制 T98G 胶质母细胞瘤细胞与纤连蛋白基质的粘附。为了阐明作用机制，我们对存在或不存在生腱蛋白-C 的情况下生长的 T89G 细胞进行了 RNA 表达分析，发现生腱蛋白-C 下调原肌球蛋白-1。原肌球蛋白-1 过表达后，细胞在纤连蛋白/腱生蛋白-C 培养基上的铺展恢复，表明腱生蛋白-C 通过下调原肌球蛋白-1 使肌动蛋白应力纤维不稳定。 Tenascin-C 还增加 A 型内皮素受体的表达，并刺激相应的丝裂原激活蛋白激酶信号通路，从而触发细胞外信号调节激酶 1/2 磷酸化和 c-Fos 表达。 Tenascin-C 还引起 Wnt 抑制剂 Dickkopf 1 的下调。因此，Wnt 信号传导通过稳定 β-连环蛋白而增强，并刺激 β-连环蛋白靶标 Id2 的表达。最后，我们从星形细胞瘤组织阵列中获得的体内数据将生腱蛋白-C 和 Id2 表达增加与高度恶性联系起来。由于内皮素和 Wnt 信号传导的增加以及原肌球蛋白-1 表达的减少与转化和肿瘤发生密切相关，因此我们建议生腱蛋白-C 特异性调节这些信号传导途径以增强神经胶质瘤细胞的增殖。
Tenascin-C is an adhesion-modulating extracellular matrix molecule that is highly expressed in tumor stroma and stimulates tumor cell proliferation. Adhesion of T98G glioblastoma cells to a fibronectin substratum is inhibited by tenascin-C. To address the mechanism of action, we performed a RNA expression analysis of T89G cells grown in the presence or absence of tenascin-C and found that tenascin-C down-regulates tropomyosin-1. Upon overexpression of tropomyosin-1, cell spreading on a fibronectin/tenascin-C substratum was restored, indicating that tenascin-C destabilizes actin stress fibers through down-regulation of tropomyosin-1. Tenascin-C also increased the expression of the endothelin receptor type A and stimulated the corresponding mitogen-activated protein kinase signaling pathway, which triggers extracellular signal-regulated kinase 1/2 phosphorylation and c-Fos expression. Tenascin-C additionally caused down-regulation of the Wnt inhibitor Dickkopf 1. In consequence, Wnt signaling was enhanced through stabilization of β-catenin and stimulated the expression of the β-catenin target Id2. Finally, our in vivo data derived from astrocytoma tissue arrays link increased tenascin-C and Id2 expression with high malignancy. Because increased endothelin and Wnt signaling, as well as reduced tropomyosin-1 expression, are closely linked to transformation and tumorigenesis, we suggest that tenascin-C specifically modulates these signaling pathways to enhance proliferation of glioma cells.