Cyclooxygenase-2 enhances α2β1 integrin expression and cell migration via EP1 dependent signaling pathway in human chondrosarcoma cells
Cyclooxygenase-2 enhances α2β1 integrin expression and cell migration via EP1 dependent signaling pathway in human chondrosarcoma cells
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DOI：
10.1186/1476-4598-9-43
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发表时间：
2010-02-23
期刊：
影响因子：
37.3
通讯作者：
Tang, Chih-Hsin
中科院分区：
文献类型：
--
作者：
Liu, Ju-Fang;Fong, Yi-Chin;Tang, Chih-Hsin
背景：环氧化酶（考克斯）-2是前列腺素（PG）合成酶的诱导型亚型，与肿瘤转移有关。据报道，考克斯-2与其在癌细胞表面上的特异性EP受体的相互作用可诱导癌症侵袭。然而，考克斯-2对人软骨肉瘤细胞迁移活性的影响大多是未知的。结果：考克斯-2过表达或外源性PGE（2）增加了人软骨肉瘤细胞的迁移能力。软骨肉瘤组织和软骨肉瘤细胞系中考克斯-2的表达明显高于正常软骨组织。通过使用药理学抑制剂或激活剂或EP受体的遗传抑制，我们发现EP 1受体而不是其他PGE受体参与PGE（2）介导的细胞迁移和α 2 β 1整合素表达。此外，我们发现，人软骨肉瘤组织表达更高水平的EP 1受体比正常软骨。磷脂酶C（PLC）、蛋白激酶C（PKC）和c-Src抑制剂可减弱PGE（2）介导的细胞迁移和整合素上调。PGE（2）处理后PLC β、PKC α、c-Src和NF-κ B信号通路被激活，PLC、PKC、c-Src和NF-κ B级联的特异性抑制剂、siRNA和突变体均抑制PGE（2）诱导的整合素表达和迁移活性。我们的研究结果表明PGE（2）通过EP 1/PLC/PKC alpha/c-Src/NF-κ B信号转导途径增加α 2 β 1整合素表达，从而增强软骨肉瘤细胞的迁移能力。
Background: Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin (PG) synthase, has been implicated in tumor metastasis. Interaction of COX-2 with its specific EP receptors on the surface of cancer cells has been reported to induce cancer invasion. However, the effects of COX-2 on migration activity in human chondrosarcoma cells are mostly unknown. In this study, we examined whether COX-2 and EP interaction are involved in metastasis of human chondrosarcoma.Results: We found that over-expression of COX-2 or exogenous PGE(2) increased the migration of human chondrosarcoma cells. We also found that human chondrosarcoma tissues and chondrosarcoma cell lines had significant expression of the COX-2 which was higher than that in normal cartilage. By using pharmacological inhibitors or activators or genetic inhibition by the EP receptors, we discovered that the EP1 receptor but not other PGE receptors is involved in PGE(2)-mediated cell migration and alpha 2 beta 1 integrin expression. Furthermore, we found that human chondrosarcoma tissues expressed a higher level of EP1 receptor than normal cartilage. PGE(2)-mediated migration and integrin up-regulation were attenuated by phospholipase C (PLC), protein kinase C (PKC) and c-Src inhibitor. Activation of the PLC beta, PKC alpha, c-Src and NF-kappa B signaling pathway after PGE(2) treatment was demonstrated, and PGE(2)-induced expression of integrin and migration activity were inhibited by the specific inhibitor, siRNA and mutants of PLC, PKC, c-Src and NF-kappa B cascades.Conclusions: Our results indicated that PGE(2) enhances the migration of chondrosarcoma cells by increasing alpha 2 beta 1 integrin expression through the EP1/PLC/PKC alpha/c-Src/NF-kappa B signal transduction pathway.