MT2-MMP induces proteolysis and leads to EMT in carcinomas

Abstract

Epithelial-mesenchymal transition (EMT) is critical for carcinoma invasiveness and metastasis. To investigate the role of membrane-type-2 matrix metalloproteinase (MT2-MMP) in EMT, we generated lentiviral constructs of wild-type (WT) and an inactive Glu260Ala (E260A) mutant MT2-MMP and derived stably transfected HCT116 and A549 cell lines. WT-transfected cells appeared mesenchymal-like, whereas cells transfected with the E260A mutant were epithelial-like, as were cells treated with an MMP inhibitor (GM6001). Expression of E-cadherin, β-catenin, and zonula occludens-1 was lower in cells transfected with WT MT2-MMP compared to vector controls, cells treated with GM6001, or cells transfected with the E260A mutant. An 80-kD N-terminal fragment of E-cadherin was immunoprecipitated in conditioned medium from WT MT2-MMP cells, but not in the medium from vector controls, cells treated with GM6001, or E260A mutant cells. When endogenous expression of MT2-MMP in A2780 human ovarian cancer cells was inhibited using GM6001 or MT2-MMP-specific siRNA, levels of the 80-kD E-cadherin fragment in conditioned medium were decreased. Chick embryo chorioallantoic membrane invasion assays demonstrated that cells transfected with WT MT2-MMP were more invasive than cells transfected with control vector, treated with GM6001, or transfected with the E260A mutant. These results suggest that MT2-MMP degrades adherens and tight junction proteins and results in EMT, making it a potential mediator of EMT in carcinomas.

SNX27–retromer assembly recycles MT1-MMP to invadopodia and promotes breast cancer metastasis

“…Also, two independent studies showed that depletion of endogenous MT1-MMP or MT2-MMP reduced the basement membrane invasive activity in the MDA-MB-231 cell line (Hotary et al, 2006;Ota et al, 2009). Further, MT2-MMP is shown to degrade E-cadherin by its proteolytic activity, leading to epithelial-mesenchymal transition, and thereby facilitates cell invasion (Liu et al, 2016). Consistent with these reports, we observed that depletion of MT2-MMP led to abrogation of Matrigel invasion activity (Fig.…”

Emodin Inhibits the Epithelial to Mesenchymal Transition of Epithelial Ovarian Cancer Cells via ILK/GSK-3β/Slug Signaling Pathway

“…What is more, the mortality of EOC is directly related to the prevalence of metastatic diseases [21]. EMT is an important process that culminates with loss of epithelial traits and gain of mesenchymal traits [22]. In recent studies, a crucial link has been discovered between the acquisition of metastatic traits in cancer cells and the EMT.…”

Mechanisms of the Epithelial–Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer

“…EMT promotes the transformation of immobile epithelial cells into motile mesenchymal cells, enhancing the metastatic properties [69,70]. Further, adherens and tight junctions become impaired, resulting in a mesenchymal phenotype [12,[71][72][73]. Altered E-and N-cadherin levels and the following β-catenin activation promote the expression of many tumor-associated proteins, including cyclin D1, CD44, or c-MYC [54,[74][75][76][77][78][79].…”