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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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EGFR-MEK/ERK signaling up-regulates the expression of EMT-associated genes
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Figure 4: EGFR-MEK/ERK signaling up-regulates the expression of EMT-associated genes

Mentions: A pronounced difference between shEcad and shCtl cells is the increased expression of ZEB1, TWIST1, and MMP2 (Figs. 1E and 2B), all of which are involved in metastasis [3, 29] and belong to ‘EMT-associated genes’ [30]. Subsequently, we examined whether the expression of these genes is associated with higher EGF responsiveness of shEcad. For this purpose, the mRNA levels of ZEB1, TWIST1, and MMP2 were determined following transient activation of EGFR-dependent signaling. Interestingly, shEcad exhibited higher responsiveness toward EGF stimulation, both at 24 hr (ZEB1) and 72 hr (TWIST1, ZEB1 and MMP2), compared to the shCtl cells (Fig. 4A).


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)

EGFR-MEK/ERK signaling up-regulates the expression of EMT-associated genes
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: EGFR-MEK/ERK signaling up-regulates the expression of EMT-associated genes
Mentions: A pronounced difference between shEcad and shCtl cells is the increased expression of ZEB1, TWIST1, and MMP2 (Figs. 1E and 2B), all of which are involved in metastasis [3, 29] and belong to ‘EMT-associated genes’ [30]. Subsequently, we examined whether the expression of these genes is associated with higher EGF responsiveness of shEcad. For this purpose, the mRNA levels of ZEB1, TWIST1, and MMP2 were determined following transient activation of EGFR-dependent signaling. Interestingly, shEcad exhibited higher responsiveness toward EGF stimulation, both at 24 hr (ZEB1) and 72 hr (TWIST1, ZEB1 and MMP2), compared to the shCtl cells (Fig. 4A).

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