Autocrine CCL2 promotes cell migration and invasion via PKC activation and tyrosine phosphorylation of paxillin in bladder cancer cells
Autocrine CCL2 promotes cell migration and invasion via PKC activation and tyrosine phosphorylation of paxillin in bladder cancer cells
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DOI：
10.1016/j.cyto.2012.04.017
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发表时间：
2012-08-01
期刊：
影响因子：
3.8
通讯作者：
Tang, Shye-Jye
中科院分区：
文献类型：
--
作者：
Chiu, Hsiao-Ying;Sun, Kuang-Hui;Tang, Shye-Jye
膀胱移行细胞癌产生的单核细胞趋化蛋白-1（MCP-1/CCL 2）的量与膀胱癌的高复发率和不良预后直接相关。然而，CCL 2对肿瘤进展的影响的潜在机制仍然未被探索。为了研究CCL 2所起的作用，我们检查了各种膀胱癌细胞系中的细胞迁移。我们发现，表达高水平CCL 2的高级别癌细胞比表达低水平趋化因子的低级别膀胱癌细胞表现出更多的迁移活性。尽管CCL 2/CCR 2信号的激活并不明显影响细胞生长，但它通过蛋白激酶C的激活和桩蛋白酪氨酸的磷酸化介导细胞迁移和侵袭。用小发夹RNA（shCCL 2）或特异性抑制剂阻断CCL 2和CCR 2可减少CCL 2/CCR 2介导的细胞迁移。CCL 2的拮抗剂促进了携带MBT 2膀胱癌细胞的小鼠的存活，并且与shGFP细胞相比，CCL 2去除的细胞显示出较低的致瘤性。除了在高级别人膀胱癌细胞中观察到高水平的CCL 2外，我们还发现CCL 2/CCR 2信号通路介导了迁移和侵袭活性，而阻断该通路可降低迁移和侵袭。总之，CCL 2在膀胱癌中的高水平表达介导了肿瘤的侵袭，并参与了晚期肿瘤的发生。我们的研究结果表明，这种CCL 2/CCR 2途径是一个潜在的候选人的衰减膀胱癌转移。(C)2012爱思唯尔有限公司保留所有权利。
The amount of monocyte chemoattractant protein-1 (MCP-1/CCL2) produced by a transitional cell carcinoma is directly correlated with high recurrence and poor prognosis in bladder cancer. However, the mechanisms underlying the effects of CCL2 on tumor progression remain unexplored. To investigate the role played by CCL2, we examined cell migration in various bladder cancer cell lines. We found that high-grade cancer cells expressing high levels of CCL2 showed more migration activity than low-grade bladder cancer cells expressing low levels of the chemokine. Although the activation of CCL2/CCR2 signals did not appreciably affect cell growth, it mediated cell migration and invasion via the activation of protein kinase C and phosphorylation of tyrosine in paxillin. Blocking CCL2 and CCR2 with small hairpin RNA (shCCL2) or a specific inhibitor reduced CCL2/CCR2-mediated cell migration. The antagonist of CCR2 promoted the survival of mice bearing MBT2 bladder cancer cells, and CCL2-depleted cells showed low tumorigenicity compared with shGFP cells. In addition to observing high-levels of CCL2 in high-grade human bladder cancer cells, we showed that the CCL2/CCR2 signaling pathway mediated migratory and invasive activity, whereas blocking the pathway decreased migration and invasion. In conclusion, high levels of CCL2 expressed in bladder cancer mediates tumor invasion and is involved with advanced tumorigenesis. Our findings suggest that this CCL2/CCR2 pathway is a potential candidate for the attenuation of bladder cancer metastases. (C) 2012 Elsevier Ltd. All rights reserved.