Src and caveolin-1 reciprocally regulate metastasis via a common downstream signaling pathway in bladder cancer.
Src and caveolin-1 reciprocally regulate metastasis via a common downstream signaling pathway in bladder cancer.
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DOI：
10.1158/0008-5472.can-10-0730
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Theodorescu D
中科院分区：
文献类型：
--
作者：
Thomas S;Overdevest JB;Nitz MD;Williams PD;Owens CR;Sanchez-Carbayo M;Frierson HF;Schwartz MA;Theodorescu D
在膀胱癌中，Caveolin-1（Cav-1）表达增加和Src表达和激酶活性降低与肿瘤侵袭性相关。在这里，我们调查的临床和功能的意义，如果有的话，这种相互表达在膀胱癌转移。我们评估了肿瘤Cav-1和Src RNA和蛋白表达的能力，以预测257例患者在两项独立的临床研究中接受cytoplasmic治疗后的结果。在这两种情况下，高Cav-1和低Src水平与转移发展相关。我们在UMUC-3和RT 4人膀胱癌细胞中过表达或耗尽Cav-1和Src蛋白水平，并评估其对肌动蛋白应力纤维、使用transwell的迁移和尾静脉接种后的肺转移的影响。在转移性UMUC-3细胞中Cav-1缺失或活性Src表达减少肌动蛋白应力纤维、细胞迁移和转移，而Cav-1过表达或Src缺失增加非转移性RT 4细胞的迁移。生化研究表明Cav-1通过其磷酸化形式（pY 14）介导这些作用，而Src作用通过p190 RhoGAP的磷酸化介导，并且这些途径会聚以降低RhoA、RhoC和Rho效应器ROCK 1的活性。用ROCK抑制剂治疗减少了体内UMUC-3肺转移，表型模拟了Cav-1耗竭或活性Src表达的作用。Src抑制膀胱癌的转移，Cav-1促进膀胱癌的转移。基于Cav-1和Src谱的个体化治疗抑制转移发展的临床评价似乎是必要的。
In bladder cancer, increased Caveolin-1 (Cav-1) expression and decreased Src expression and kinase activity correlate with tumor aggressiveness. Here, we investigate the clinical and functional significance if any, of this reciprocal expression in bladder cancer metastasis. We evaluated the ability of tumor Cav-1 and Src RNA and protein expression to predict outcome following cystectomy in 257 patients enrolled in two independent clinical studies. In both, high Cav-1 and low Src levels were associated with metastasis development. We overexpressed or depleted Cav-1 and Src protein levels in UMUC-3 and, RT4 human bladder cancer cells and evaluated the effect of this on actin stress fibers, migration using transwells and lung metastasis following tail vein inoculation. Cav-1 depletion or expression of active Src in metastatic UMUC-3 cells decreases actin stress fibers, cell migration and metastasis, while, Cav-1 overexpression or Src depletion increased the migration of non-metastatic RT4 cells. Biochemical studies indicated Cav-1 mediates these effects via its phosphorylated form (pY14), whereas Src effects are mediated through phosphorylation of p190RhoGAP and these pathways converge to reduce activity of RhoA, RhoC and Rho effector ROCK1. Treatment with a ROCK inhibitor reduced UMUC-3 lung metastasis in vivo, phenocopying the effect of Cav-1 depletion or expression of active Src. Src suppresses while Cav-1 promotes metastasis of bladder cancer through a pharmacologically tractable common downstream signaling pathway. Clinical evaluation of personalized therapy to suppress metastasis development based on Cav-1 and Src profiles appears warranted.