Caveolin-1 up-regulation during epithelial to mesenchymal transition is mediated by focal adhesion kinase
Caveolin-1 up-regulation during epithelial to mesenchymal transition is mediated by focal adhesion kinase
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DOI：
10.1074/jbc.m709329200
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发表时间：
2008-05-16
影响因子：
4.8
通讯作者：
Liu, Jun
中科院分区：
文献类型：
--
作者：
Bailey, Kelly M.;Liu, Jun
新出现的证据表明，小窝蛋白-1在许多转移性癌症中上调，并且可以影响细胞迁移的各个方面。然而，一般来说，小窝蛋白-1在癌症进展中的作用知之甚少。在本研究中，我们研究了上皮间质转化（EMT）过程中小窝蛋白-1表达的变化以及小窝蛋白-1改变癌细胞粘附（细胞运动的一个方面）的能力。我们采用了两种EMT细胞模型，人胚胎癌细胞系NT 2/D1和TGF-β 1处理的NMuMG细胞，它们来自正常小鼠乳腺上皮。小窝蛋白-1的表达在诱导EMT后的两种细胞系中均显著上调，并且在此之前，粘着斑激酶（FAK）和Src（两种已知的参与EMT的酪氨酸激酶）的活化增加。我们假设小窝蛋白-1的表达可能受到FAK磷酸化增加的影响，Src是已知的贡献者。对FAK（+/+）和FAK（+/+）小鼠胚胎成纤维细胞的检查显示，在缺乏FAK的细胞中，小窝蛋白-1表达显著减少。使用FAK和superFAK构建体以及新型FAK抑制剂PF-228，我们能够证明FAK确实可以调节小窝蛋白-1的表达。我们还发现，Src可以有助于增加小窝蛋白-1的表达，但是，只有在FAK的存在。从这些数据的结果和我们的功能分析，我们得出结论，小窝蛋白-1的表达可以上调EMT过程中，而且，一旦表达，小窝蛋白-1可以极大地影响癌细胞的粘附。
Emerging evidence has shown that caveolin-1 is up-regulated in a number of metastatic cancers and can influence various aspects of cell migration. However, in general, the role of caveolin-1 in cancer progression is poorly understood. In the present study, we examined alterations in caveolin-1 expression during epithelial-to-mesenchymal transition (EMT) and the ability of caveolin-1 to alter cancer cell adhesion, an aspect of cell motility. We employed two EMT cell models, the human embryonic carcinoma cell line NT2/D1, and TGF-beta 1-treated NMuMG cells, which are derived from normal mouse mammary epithelia. Caveolin-1 expression was substantially upregulated in both cell lines following the induction of EMT and was preceded by increased activation of focal adhesion kinase (FAK) and Src, two known tyrosine kinases involved in EMT. We hypothesized that caveolin-1 expression could be influenced by increased FAK phosphorylation, to which Src is a known contributor. Examination of FAK(+/+) and FAK(+/+) mouse embryonic fibroblasts revealed that in cells devoid of FAK, caveolin-1 expression is strikingly diminished. Using FAK and superFAK constructs and the novel FAK inhibitor PF-228, we were able to demonstrate that indeed, FAK can regulate caveolin-1 expression. We also found that Src can contribute to increases in caveolin-1 expression, however, only in the presence of FAK. From the culmination of this data and our functional analyses, we conclude that caveolin-1 expression can be up-regulated during EMT, and further, once expressed, caveolin-1 can greatly influence cancer cell adhesion.