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Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer.

Bae GY, Choi SJ, Lee JS, Jo J, Lee J, Kim J, Cha HJ - Oncotarget (2013)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Sogang University, Seoul, Republic of Korea.

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.

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Related in: MedlinePlus

Knockdown of E-cadheirn induces the EMT in A549 cells
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Figure 1: Knockdown of E-cadheirn induces the EMT in A549 cells

Mentions: To investigate the effect of E-cadherin on the EMT process in A549 NSCLC cells, the E-cadherin knockdown cell line (E-cad KD: shEcad) was generated by the stable expression of E-cadherin shRNA. The E-cad KD A549 cells showed dramatic morphological changes compared to the shRNA control A549 cells (shCtl). The mesenchymal features such as loss of cell polarity, spindle-like cell shape and loss of cell-to-cell adhesion were distinct in shEcad, whereas the epithelial characteristics such as close cell-to-cell adhesion and cobblestone-like cell shape were still observed in shCtl (Fig. 1A). Additionally, the E-cadherin signal clearly observed at the boundaries of shCtl was abolished in shEcad, indicating that altered cell-to-cell adhesion in shEcad is associated with the loss of E-cadherin (Fig. 1B). In the characteristic EMT process, loss of E-cadherin is accompanied with gain of N-cadherin, which is known as the ‘E- to N-cadherin switching’ [4] (Fig. 1C). In addition to morphological changes, mesenchymal genes such as CDH2 (encoding N-cadherin) and VIMENTIN (encoding Vimentin) but not ACTA2 (encoding α-smooth muscle actin; SMA) were clearly upregulated (Fig. 1D). Of note, 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). This result is in agreement with an earlier study in breast cancer cells showing that the loss of E-cadherin is sufficient to alter the wide range of transcriptional changes, including changes in TWIST1 and ZEB1 [6], implying that both TWIST1 and ZEB1 could be the common EMT-inducing regulators in E-cadherin knockdown cancer cells.


Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer.

Bae GY, Choi SJ, Lee JS, Jo J, Lee J, Kim J, Cha HJ - Oncotarget (2013)

Knockdown of E-cadheirn induces the EMT in A549 cells
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926845&req=5

Figure 1: Knockdown of E-cadheirn induces the EMT in A549 cells
Mentions: To investigate the effect of E-cadherin on the EMT process in A549 NSCLC cells, the E-cadherin knockdown cell line (E-cad KD: shEcad) was generated by the stable expression of E-cadherin shRNA. The E-cad KD A549 cells showed dramatic morphological changes compared to the shRNA control A549 cells (shCtl). The mesenchymal features such as loss of cell polarity, spindle-like cell shape and loss of cell-to-cell adhesion were distinct in shEcad, whereas the epithelial characteristics such as close cell-to-cell adhesion and cobblestone-like cell shape were still observed in shCtl (Fig. 1A). Additionally, the E-cadherin signal clearly observed at the boundaries of shCtl was abolished in shEcad, indicating that altered cell-to-cell adhesion in shEcad is associated with the loss of E-cadherin (Fig. 1B). In the characteristic EMT process, loss of E-cadherin is accompanied with gain of N-cadherin, which is known as the ‘E- to N-cadherin switching’ [4] (Fig. 1C). In addition to morphological changes, mesenchymal genes such as CDH2 (encoding N-cadherin) and VIMENTIN (encoding Vimentin) but not ACTA2 (encoding α-smooth muscle actin; SMA) were clearly upregulated (Fig. 1D). Of note, 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). This result is in agreement with an earlier study in breast cancer cells showing that the loss of E-cadherin is sufficient to alter the wide range of transcriptional changes, including changes in TWIST1 and ZEB1 [6], implying that both TWIST1 and ZEB1 could be the common EMT-inducing regulators in E-cadherin knockdown cancer cells.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Sogang University, Seoul, Republic of Korea.

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.

Show MeSH
Related in: MedlinePlus