Abstract
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 NSCLS 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 NSCSLs.
Highlights
epithelial-mesenchymal transition (EMT) is a highly conserved developmental process, in which a polarized epithelial cell acquires the properties of a mesenchymal cell during embryonic development [1]
We found that the epidermal growth factor receptor (EGFR)-MEK/ERK signaling is aberrantly activated by simple depletion of E-cadherin, and is closely associated to invasion in matrix metalloproteinase-2 (MMP2) dependent manner
A simple E-cadherin knockdown was able to promote the expression of several transcription factors such as TWIST1, SLUG, and ZEB1, which serve as typical EMT inducers [14] (Fig. 1E)
Summary
EMT is a highly conserved developmental process, in which a polarized epithelial cell acquires the properties of a mesenchymal cell during embryonic development [1]. Besides role during development, EMT is well-characterized in malignant tumor progression, metastasis [2] and even acquisition of cancer stemness [3]. The loss of E-cadherin expression, a prototypical marker of EMT [2], is frequently found in various metastatic human epithelial cancers [4]. The promotion of metastasis by the loss of E-cadherin has been shown to result from the activation of intracellular signaling and subsequent up-regulation of transcription factors [5, 6]. The aberrant activation of epidermal growth factor receptor (EGFR) signaling contributes to NSCLC progression and is highly correlated with poor prognosis [7]. EGFR ligands such as epidermal growth factor (EGF) and transforming growth factor-α (TGFα) are frequently www.impactjournals.com/oncotarget
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