Cysteine-rich 61 (CCN1) enhances chemotactic migration, tran send othelial cell migration, and intravasation by concomitantly up-regulating chemokine receptor 1 and 2
Cysteine-rich 61 (CCN1) enhances chemotactic migration, tran send othelial cell migration, and intravasation by concomitantly up-regulating chemokine receptor 1 and 2
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DOI：
10.1158/1541-7786.mcr-06-0289
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发表时间：
2007-11-01
影响因子：
5.2
通讯作者：
Lin, Ming-Tsan
中科院分区：
文献类型：
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作者：
Lin, Been-Ren;Chang, Cheng-Chi;Lin, Ming-Tsan
富含半胱氨酸的 61（Cyr61；CCN1）在多种人类恶性肿瘤的发生和进展中发挥着重要作用。在这里，我们进一步证明了 Cyr61 基因的强制表达或重组 Cyr61 蛋白的治疗增强了胃癌 AGS 细胞中趋化因子受体 CXCR1 和 CXCR2 的表达。通过转染反义 Cyr61 来减弱 MKN-45 细胞中的 Cyr61 水平，从而显着降低 CXCR1 和 CXCR2 的水平。表明Cyr61在胃癌细胞中严格调控下游基因CXCR1和CXCR2。人胃腺癌的逆转录PCR和免疫组织化学分析显示Cyr61和CXCR1/CXCR2的表达水平之间存在高度相关性。 Cyr61 过表达 AGS 细胞中 CXCR1 和 CXCR2 功能的上调可促进其向白细胞介素 8（CXCR1 和 CXCR2 的生理配体）趋化迁移。此外，Cyr61 介导的 CXCR1/CXCR2 上调也有助于跨内皮迁移以及鸡胚胎模型中的内渗。药理学和遗传学方法表明，磷酸肌醇 3 激酶 (PI3K)/Akt，而非细胞外信号调节激酶 1/2 或 p38，信号通路是 Cyr61 诱导的 CXCR1/CXCR2 mRNA 和蛋白上调所必需的。针对整合素 alpha v beta 3（而非 alpha(2)beta(1)）的功能中和抗体可有效消除 Cyr61 引发的 Src 激活以及随后的 PI3K/Akt 通路。整合素 α v β 3、Src 激酶和 PI3K/Akt 的拮抗剂不仅抑制 CXCR1/CXCR2 升高，还阻断 Cyr61 诱导的趋化迁移。总之，我们认为 Cyr61 通过整合素 α v β 3/Src/PI3K/Akt 依赖性途径诱导 CXCR1/CXCR2，从而促进白细胞介素 8 依赖性趋化性、跨内皮迁移和内渗。
Cysteine-rich 61 (Cyr61; CCN1) plays an important role in tumor development and progression in many kinds of human malignancies. Here, we further show the enforced expression of the Cyr61 gene or treatment with recombinant Cyr61 protein enhanced expression of chemokine receptors CXCR1 and CXCR2 in gastric cancer AGS cells. Attenuation of Cyr61 levels in MKN-45 cells by transfecting with antisense Cyr61 significantly reduced the level of CXCR1 and CXCR2. It is suggested that Cyr61 tightly regulates the downstream genes CXCR1 and CXCR2 in gastric cancer cells. Supportively, reverse transcription-PCR and immunohistochemical analysis of human gastric adenocarcinoma showed that there was a high correlation between the expression level of Cyr61 and CXCR1/CXCR2. The up-regulated functionality of CXCR1 andCXCR2 in Cyr61-overexpressing AGS cells could facilitate their chemotactic migration toward interleukin-8, a physiologic ligand of CXCR1 and CXCR2. In addition, the Cyr61-mediated up-regulation of CXCR1/CXCR2 also contributed to transendothelial migration, as well as intravasation in a chick embryo model. Pharmacologic and genetic approaches revealed that phosphoinositide 3-kinase (PI3K)/Akt, but not extracellular signal-regulated kinase 1/2 or p38, signaling pathway is requisite for the up-regulation of CXCR1/CXCR2 mRNA and protein induced by Cyr61. Function-neutralizing antibody to integrin alpha v beta 3, but not alpha(2)beta(1), effectively abolished Cyr61-elicited Src activation and the subsequent PI3K/Akt pathway. Antagonists toward integrin alpha v beta 3, Src kinase, and PI3K/Akt not only suppressed CXCR1/ CXCR2 elevation but also blocked chemotactic migration induced by Cyr61. In conclusion, we suggest that Cyr61 promotes interleukin-8-dependent chemotaxis, transendothelial migration, and intravasation by induction of CXCR1/CXCR2 through integrin alpha v beta 3/Src/PI3K/Akt-dependent pathway.