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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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Inhibition of MEK/ERK signaling reduces the EMT phenotypes of shEcad
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Figure 5: Inhibition of MEK/ERK signaling reduces the EMT phenotypes of shEcad

Mentions: On the basis of MEK/ERK signaling-dependent MMP2 induction (Fig. 4C), which was closely associated with the elevated invasive behavior of shEcad cells (Fig. 2), it is readily surmised that the invasiveness of shEcad may result from an activated MEK/ERK axis due to higher and/or more sustained EGFR activation. To examine this hypothesis, the invasive activity of shEcad cells was determined following PD treatment. As predicted, the enhanced invasion of shEcad cells (Fig. 2A) was noticeably abolished by a single treatment of PD (Fig. 5A). To rule out non-specific effects of PD, other than inhibition of MEK activity toward ERK, ERK1 and 2 were depleted with siRNAs to monitor the invasive character in shEcad. Consistent with the results observed with PD treatment, simultaneous depletion of ERK1 and 2 clearly attenuated the enhanced invasive property of shEcad (Fig. 5B). As the enhanced invasive property of shEcad results from the induction of MMP2 (Fig. 2), we predicted that the reduced invasion of shEcad after PD treatment (Fig. 5A) or ERK1 and 2 depletion (Fig. 5B) was accompanied with the suppression of MMP2, the expression of which is in turn dependent on the MEK/ERK axis (Fig. 4C).


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)

Inhibition of MEK/ERK signaling reduces the EMT phenotypes of shEcad
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Inhibition of MEK/ERK signaling reduces the EMT phenotypes of shEcad
Mentions: On the basis of MEK/ERK signaling-dependent MMP2 induction (Fig. 4C), which was closely associated with the elevated invasive behavior of shEcad cells (Fig. 2), it is readily surmised that the invasiveness of shEcad may result from an activated MEK/ERK axis due to higher and/or more sustained EGFR activation. To examine this hypothesis, the invasive activity of shEcad cells was determined following PD treatment. As predicted, the enhanced invasion of shEcad cells (Fig. 2A) was noticeably abolished by a single treatment of PD (Fig. 5A). To rule out non-specific effects of PD, other than inhibition of MEK activity toward ERK, ERK1 and 2 were depleted with siRNAs to monitor the invasive character in shEcad. Consistent with the results observed with PD treatment, simultaneous depletion of ERK1 and 2 clearly attenuated the enhanced invasive property of shEcad (Fig. 5B). As the enhanced invasive property of shEcad results from the induction of MMP2 (Fig. 2), we predicted that the reduced invasion of shEcad after PD treatment (Fig. 5A) or ERK1 and 2 depletion (Fig. 5B) was accompanied with the suppression of MMP2, the expression of which is in turn dependent on the MEK/ERK axis (Fig. 4C).

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