Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer.
Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer.
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DOI：
10.18632/oncotarget.1463
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发表时间：
2013-12
期刊：
影响因子：
--
通讯作者：
Cha HJ
中科院分区：
文献类型：
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作者：
Bae GY;Choi SJ;Lee JS;Jo J;Lee J;Kim J;Cha HJ
E-钙粘附素的缺失是上皮-间充质转化(EMT)的一个标志，它可以显著影响转移转移。然而，非小细胞肺癌(NSCLC)中E-钙粘附素缺失导致EMT相关转移的分子机制仍不清楚。在目前的研究中，我们发现E-钙粘附素的敲除足以将A549非小细胞肺癌细胞转化为间叶型，同时典型的EMT诱导剂如ZEB1和Twist1同时上调。有趣的是，E-钙粘附素缺失诱导的EMT诱导的细胞以依赖基质金属蛋白酶-2(MMP2)的方式促进侵袭，并异常激活EGFR信号。我们证明，侵袭力的增加是EGFR-MEK/ERK信号激活的结果，而EGFR-MEK/ERK信号又导致ZEB1依赖的MMP2诱导。这些结果提示，EGFR-MEK/ERK/ZEB1/MMP2轴在EMT诱导的NSCLC侵袭中起促进作用。在非小细胞肺癌组织中，ERK的激活和E-钙粘附素的丢失均见于浸润性肿瘤前沿的癌细胞。因此，EGFR-MEK/ERK信号通路有望成为控制EMT诱导的NSCLC MMP2异常表达和侵袭的分子靶点。
Loss of E-cadherin, a hallmark of epithelial-mesenchymal transition (EMT), can significantly affect metastatic dissemination. However, the molecular mechanism of EMT-associated metastatic dissemination by loss of E-cadherin still remains unclear in non-small cell lung cancers (NSCLCs). In the present study, we show that the knockdown of E-cadherin was sufficient to convert A549 NSCLC cells into mesenchymal type with the concurrent up-regulation of typical EMT inducers such as ZEB1 and TWIST1. Interestingly, the EMT-induced cells by E-cadherin depletion facilitate invasion in a matrix metalloproteinase-2 (MMP2)-dependent manner with aberrant activation of EGFR signaling. We demonstrated that the elevated invasiveness was a result of the activated EGFR-MEK/ERK signaling, which in turn leads to ZEB1 dependent MMP2 induction. These results suggest that the EGFR-MEK/ERK/ZEB1/MMP2 axis is responsible for promoted invasion in EMT-induced NSCLCs. Consistently, ERK activation and loss of E-cadherin were both observed in the disseminating cancer cells at the invasive tumor fronts in NSCLC cancer tissues. Thereby, these data suggest that the EGFR-MEK/ERK signaling would be a promising molecular target to control aberrant MMP2 expression and consequent invasion in the EMT-induced NSCLCs