title: Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer.
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.
authors: Department of Life Science, Sogang University, Seoul, Republic of Korea.
authors: Gab-Yong
authors: GY
authors: Bae
authors: So-Jung
authors: SJ
authors: Choi
authors: Ji-Seon
authors: JS
authors: Lee
authors: Jisuk
authors: J
authors: Jo
authors: Jinseon
authors: J
authors: Lee
authors: Jhingook
authors: J
authors: Kim
authors: Hyuk-Jin
authors: HJ
authors: Cha
mesh_terms: D015820:Cadherins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*
chemical_list: D015820:Cadherins; C512478:EGFR protein, human; D066246:ErbB Receptors; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2