Constitutively active MEK1 is sufficient to induce epithelial-to-mesenchymal transition in intestinal epithelial cells and to promote tumor invasion and metastasis
Constitutively active MEK1 is sufficient to induce epithelial-to-mesenchymal transition in intestinal epithelial cells and to promote tumor invasion and metastasis
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DOI：
10.1002/ijc.24485
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发表时间：
2009-10-01
影响因子：
6.4
通讯作者：
Rivard, Nathalie
中科院分区：
文献类型：
--
作者：
Lemieux, Etienne;Bergeron, Sebastien;Rivard, Nathalie
MAP激酶激酶MEK 1的组成性激活诱导肠上皮细胞的致癌转化。细胞-细胞粘附的丧失，随后上皮结构的解离是细胞运动性增加和肿瘤侵袭的先决条件。这种表型转换被称为上皮-间充质转化（EMT）。EMT在确定肿瘤的扩散方面也起重要作用。然而，MEK 1在肠EMT、肿瘤侵袭和转移中的作用尚未阐明。为了确定活化的MEK 1在肠肿瘤发生中的功能，我们建立了过表达野生型MEK 1（wtMEK）或活化的MEK 1（caMEK）的肠上皮细胞系。我们的研究结果表明，表达的caMEK是足以诱导EMT的N-钙粘蛋白，波形蛋白，蜗牛和蜗牛2的诱导证实，而减少E-钙粘蛋白，occludin，ZO-1和皮质F-肌动蛋白被注意到。Snail和Snail 2启动子分析显示，Egr-1和Fra-1，AP-1蛋白，分别负责MEK 1诱导的Snail和Snail 2表达。与表达wtMEK的细胞相比，表达活化的MEK 1的细胞明显获得了侵入能力。酶谱研究证实了在表达caMEK的细胞的培养基中MMP 2和MMP 9活性水平升高。重要的是，表达活化的MEK 1的细胞诱导肿瘤的潜伏期短，这与它们诱导体内实验转移和表达已知促进结直肠癌细胞转移的因子的能力相关。总之，我们的研究结果首次证明，肠上皮细胞中MEK 1的组成性激活足以诱导与肿瘤侵袭和转移相关的EMT。(C)2009年UICC
Constitutive activation of the MAP kinase kinase MEK1 induces oncogenic transformation in intestinal epithelial cells. Loss of cell-cell adhesion followed by the dissociation of epithelial structures is a prerequisite for increased cell motility and tumor invasion. This phenotypic switch is designated epithelial-to-mesenchymal transition (EMT). EMT also plays an important role in deter-mining the dissemination of tumors. However, the role of MEK1 in intestinal EMT, tumor invasion and metastasis has not been elucidated. To determine the functions of activated MEK1 in intestinal tumorigenesis, we established intestinal epithelial cell lines that overexpress wild-type MEK1 (wtMEK) or activated MEK1 (caMEK). Our results indicate that expression of caMEK is sufficient to induce EMT as confirmed with the induction of N-cadherin, vimentin, Snaill and Snail2, whereas a reduction in E-cadherin, occludin, ZO-1 and cortical F-actin was noted. The Snaill and Snail2 promoter analyses revealed that Egr-1 and Fra-1, an AP-1 protein, are responsible for MEK1-induced Snaill and Snail2 expression, respectively. Cells expressing activated MEK1 clearly acquired an invasive capacity when compared to wtMEK-expressing cells. Zymography studies confirmed elevated levels of MMP2 and MMP9 activities in media of caMEK-expressing cells. Importantly, cells expressing activated MEK1 induced tumors with short latency in correlation with their ability to induce experimental metastasis in vivo and to express factors known to promote colorectal cancer cell metastasis. In conclusion, our results demonstrate, for the first time, that constitutive activation of MEK1 in intestinal epithelial cells is sufficient to induce an EMT associated with tumor invasion and metastasis. (C) 2009 UICC