Epilysin (MMP-28) induces TGF-β mediated epithelial to mesenchymal transition in lung carcinoma cells

Abstract

Epilysin (MMP-28) is the newest member of the matrix metalloproteinase (MMP) family. Although it is expressed in a number of tissues, no biological substrates or functions for this enzyme have been identified yet. We have expressed recombinant epilysin in A549 lung adenocarcinoma cells and found that this resulted in stable and irreversible epithelial to mesenchymal transition (EMT) accompanied by loss of cell surface E-cadherin, proteolytic processing of latent TGF-β-complexes and increased levels of active TGF-β. The cascade of events leading to the onset of EMT is prevented by the MMP inhibitor GM6001 or antibodies neutralizing the activity of TGF-β. Once EMT had occurred the cell phenotype could, however, not be reversed by the MMP-inhibitor. Importantly, the expression of epilysin also resulted in upregulation of MT1-MMP and gelatinase-B (MMP-9) and in the collagen invasive activity of A549 cells. Further, we found that epilysin and the recombinant hemopexin domain were targeted to the surface of epithelial cells. This cell surface interaction was sensitive to the proteolytic activity of MT1-MMP, and was lost after EMT. Current results indicate that epilysin can induce EMT and cell invasion through a TGF-β-dependent mechanism suggesting novel biological roles for this enzyme in the regulation of epithelial cell function and in the induction of carcinogenesis.