Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression.
Extracellular signal-regulated kinase signaling pathway regulates breast cancer cell migration by maintaining slug expression.
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DOI：
10.1158/0008-5472.can-09-1950
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发表时间：
2009-12-15
期刊：
影响因子：
11.2
通讯作者：
Huang S
中科院分区：
文献类型：
--
作者：
Chen H;Zhu G;Li Y;Padia RN;Dong Z;Pan ZK;Liu K;Huang S
细胞迁移是癌细胞侵袭的关键步骤。最近的研究表明ERK信号通路在癌细胞迁移中的重要性。然而，与ERK调节的细胞迁移相关的机制知之甚少。使用一组乳腺癌细胞系，我们检测到ERK活性和细胞迁移之间的良好相关性。有趣的是，我们注意到，需要48小时的治疗与U 0126（特异性MEK 1/2抑制剂）显着抑制乳腺癌细胞迁移，而这种抑制剂阻断ERK活性在1小时内。这一观察表明，ERK依赖的基因表达，而不是直接ERK信号是必不可少的细胞迁移。在进一步的研究中，我们发现ERK活性促进了AP 1组分Fra-1和c-Jun的表达，这两种组分都是细胞迁移所必需的。U 0126处理和Fra-1/c-Jun敲低的组合与单独使用相比没有产生细胞迁移的进一步减少，表明ERK和Fra-1/c-Jun以相同的机制促进细胞迁移。在试图研究Fra-1/c-Jun在细胞迁移中的作用时，我们发现ERK-Fra-1/c-Jun轴以AP 1依赖的方式调节slug表达。此外，U 0126诱导的迁移抑制的发生与蛞蝓减少相一致，沉默蛞蝓表达废除了乳腺癌细胞的迁移。这些结果表明ERK调节的细胞迁移和蛞蝓表达之间的关联。事实上，在表达蛞蝓转基因的细胞中，U 0126处理或Fra-1/c-Jun沉默并未显著抑制细胞迁移。我们的研究表明ERK通路通过维持slug表达来调节乳腺癌细胞迁移。
Cell migration is a critical step in cancer cell invasion. Recent studies have implicated the importance of the ERK signaling pathway in cancer cell migration. However, the mechanism associated with ERK-regulated cell migration is poorly understood. Using a panel of breast cancer cell lines, we detected an excellent correlation between ERK activity and cell migration. Interestingly, we noticed that a 48-hr treatment with U0126 (specific MEK1/2 inhibitor) was needed to significantly inhibit breast cancer cell migration while this inhibitor blocked ERK activity within 1 hr. This observation suggests that ERK-dependent gene expression rather than direct ERK signaling is essential for cell migration. In further study, we found that ERK activity promoted the expression of AP1 components Fra-1 and c-Jun, both of which were necessary for cell migration. Combination of U0126 treatment and Fra-1/c-Jun knockdown did not yield further reduction in cell migration than either alone, indicating that ERKs and Fra-1/c-Jun act in the same mechanism to facilitate cell migration. In an attempt to investigate the role of Fra-1/c-Jun in cell migration, we found that ERK-Fra-1/c-Jun axis regulated slug expression in an AP1-dependent manner. Moreover, the occurrence of U0126-induced migratory inhibition coincided with slug reduction, and silencing slug expression abrogated breast cancer cell migration. These results suggest an association between ERK-regulated cell migration and slug expression. Indeed, cell migration was not significantly inhibited by U0126 treatment or Fra-1/c-Jun silencing in cells expressing slug transgene. Our study suggests that the ERK pathway regulates breast cancer cell migration by maintaining slug expression.