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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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Disseminating tumor cells at the marginal regions of tumors exhibit loss of E-cadherin and ERK activation
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Figure 7: Disseminating tumor cells at the marginal regions of tumors exhibit loss of E-cadherin and ERK activation

Mentions: As the aberrant ERK activation is considered as an important signature in the EMT-associated invasion process, as well as the expression of ZEB1, TWIST1 and MMP2 in in vitro model, we assumed that the status of E-cadherin and ERK is an applicable index to represent the EMT-associated phenotypes in NSCLCs. To validate this idea, we analyzed the expression pattern of E-cadherin and phospho-ERK1/2 in 34 tissue specimens of NSCLC patients to assess the relationship between loss of E-cadherin and the extent of activated ERK1/2. In normal lung tissues, E-cadherin expression was distinct, whereas phospho-ERK1/2 staining was not observed in the normal epithelial cells (Fig. 7A). In cancer tissues, the staining patterns of E-cadherin and phospho-ERK1/2 appeared to be more complicated. Like normal tissues, tumor cells exhibited well-organized epithelial phenotypes, showing close cell-to-cell adhesion and abundant expression of E-cadherin (Fig. 7B). As similar as shown in a previous report [16], however, a close examination revealed that loss of E-cadherin expression frequently observed at the locally advancing marginal regions of tumors, wherein “detachment of small cell clusters” [16] was observed (Fig. 7B, red square boxes). Of note, E-cadherin expression was partially or completely lost in ‘detaching tumor cells’ (Fig. 7B, arrows) and ‘isolated tumor cells’ (Fig. 7B, arrowheads), which is consistent with the case of ‘disseminating tumor cells’ at the invasive tumor fronts [16]. When the tumor marginal regions (22 cases) were more closely examined, loss of E-cadherin was observed in all of the disseminating tumor cells (e.g. detaching tumor cells and isolated tumor cells). Of note, the disseminating tumor cells appeared to lose cell polarity and orientation, indicating EMT phenotypes. In agreement with a previous study [16], our observation suggested that the loss of E-cadherin at the invasive tumor fronts, which is accompanied by acquisition of mesenchyme-like phenotypes, might be necessary for the early stage of metastasis, including dissociation, invasion and migration.


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)

Disseminating tumor cells at the marginal regions of tumors exhibit loss of E-cadherin and ERK activation
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Disseminating tumor cells at the marginal regions of tumors exhibit loss of E-cadherin and ERK activation
Mentions: As the aberrant ERK activation is considered as an important signature in the EMT-associated invasion process, as well as the expression of ZEB1, TWIST1 and MMP2 in in vitro model, we assumed that the status of E-cadherin and ERK is an applicable index to represent the EMT-associated phenotypes in NSCLCs. To validate this idea, we analyzed the expression pattern of E-cadherin and phospho-ERK1/2 in 34 tissue specimens of NSCLC patients to assess the relationship between loss of E-cadherin and the extent of activated ERK1/2. In normal lung tissues, E-cadherin expression was distinct, whereas phospho-ERK1/2 staining was not observed in the normal epithelial cells (Fig. 7A). In cancer tissues, the staining patterns of E-cadherin and phospho-ERK1/2 appeared to be more complicated. Like normal tissues, tumor cells exhibited well-organized epithelial phenotypes, showing close cell-to-cell adhesion and abundant expression of E-cadherin (Fig. 7B). As similar as shown in a previous report [16], however, a close examination revealed that loss of E-cadherin expression frequently observed at the locally advancing marginal regions of tumors, wherein “detachment of small cell clusters” [16] was observed (Fig. 7B, red square boxes). Of note, E-cadherin expression was partially or completely lost in ‘detaching tumor cells’ (Fig. 7B, arrows) and ‘isolated tumor cells’ (Fig. 7B, arrowheads), which is consistent with the case of ‘disseminating tumor cells’ at the invasive tumor fronts [16]. When the tumor marginal regions (22 cases) were more closely examined, loss of E-cadherin was observed in all of the disseminating tumor cells (e.g. detaching tumor cells and isolated tumor cells). Of note, the disseminating tumor cells appeared to lose cell polarity and orientation, indicating EMT phenotypes. In agreement with a previous study [16], our observation suggested that the loss of E-cadherin at the invasive tumor fronts, which is accompanied by acquisition of mesenchyme-like phenotypes, might be necessary for the early stage of metastasis, including dissociation, invasion and migration.

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