环氧化酶-2 通过 EP1 依赖性信号通路增强人软骨肉瘤细胞中 α2β1 整合素的表达和细胞迁移。

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 PGE2 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 PGE2-mediated cell migration and alpha2beta1 integrin expression. Furthermore, we found that human chondrosarcoma tissues expressed a higher level of EP1 receptor than normal cartilage. PGE2-mediated migration and integrin up-regulation were attenuated by phospholipase C (PLC), protein kinase C (PKC) and c-Src inhibitor. Activation of the PLCbeta, PKCalpha, c-Src and NF-kappaB signaling pathway after PGE2 treatment was demonstrated, and PGE2-induced expression of integrin and migration activity were inhibited by the specific inhibitor, siRNA and mutants of PLC, PKC, c-Src and NF-kappaB cascades.

CONCLUSIONS

Our results indicated that PGE2 enhances the migration of chondrosarcoma cells by increasing alpha2beta1 integrin expression through the EP1/PLC/PKCalpha/c-Src/NF-kappaB signal transduction pathway.

背景

环氧化酶（COX）-2，前列腺素（PG）合酶的诱导型同工酶，已被牵连到肿瘤转移中。据报道，COX-2 与其在癌细胞表面的特定 EP 受体相互作用会诱导癌症侵袭。然而，COX-2 对人软骨肉瘤细胞迁移活性的影响在很大程度上尚不清楚。在这项研究中，我们研究了 COX-2 和 EP 相互作用是否参与人软骨肉瘤的转移。

结果

我们发现 COX-2 的过表达或外源性 PGE2 增加了人软骨肉瘤细胞的迁移。我们还发现，人软骨肉瘤组织和软骨肉瘤细胞系具有显著的 COX-2 表达，高于正常软骨。通过使用药理学抑制剂或激动剂或通过 EP 受体的遗传抑制，我们发现 EP1 受体而不是其他 PGE 受体参与 PGE2 介导的细胞迁移和α2β1 整合素表达。此外，我们发现人软骨肉瘤组织表达的 EP1 受体水平高于正常软骨。PGE2 介导的迁移和整合素上调被磷脂酶 C（PLC）、蛋白激酶 C（PKC）和 c-Src 抑制剂减弱。在用 PGE2 处理后，证明了 PLCβ、PKCalpha、c-Src 和 NF-κB 信号通路的激活，并且 PGE2 诱导的整合素表达和迁移活性被 PLC、PKC、c-Src 和 NF-κB 级联的特异性抑制剂、siRNA 和突变体抑制。