MT2-MMP induces proteolysis and leads to EMT in carcinomas
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Yusi Liu1,*, Xiaojiao Sun2,*, Jinfa Feng3,*, Li-Li Deng4, Yihao Liu1, Bokang Li1, Mingyue Zhu1, Changlian Lu1, Lingyun Zhou5
1Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, China
2Department of Pathophysiology, Harbin Medical University, Harbin, China
3Department of General Surgery, Heilongjiang Province Hospital, Harbin, China
4Department of Oncology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
5Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin, China
*These authors have contributed equally to this work
Changlian Lu, email: [email protected]
Lingyun Zhou, email: [email protected]
Keywords: MT2-MMP, cancer, epithelial-mesenchymal transition (EMT), E-cadherin, zonula occludens-1 (ZO-1)
Received: January 20, 2016 Accepted: June 09, 2016 Published: June 21, 2016
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.
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