期刊
ONCOTARGET
卷 4, 期 12, 页码 2512-2522出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1463
关键词
E-Cadherin; EGFR-MEK/ERK signaling; ZEB1; MMP2; Invasion
资金
- National Research Foundation of Korea (NRF) [2009-0093822, 2013-023601]
- Converging Research Center Program [2013K000274]
- Korean government (Minister of Science, Information and Communications Technology, and Future Planning)
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
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