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TIMP-1 induces an EMT-like phenotypic conversion in MDCK cells independent of its MMP-inhibitory domain.
- Source :
-
PloS one [PLoS One] 2012; Vol. 7 (6), pp. e38773. Date of Electronic Publication: 2012 Jun 11. - Publication Year :
- 2012
-
Abstract
- Matrix metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs) regulate epithelial-mesenchymal transition (EMT) critical for the development of epithelial organs as well as cancer cell invasion. TIMP-1 is frequently overexpressed in several types of human cancers and serves as a prognostic marker. The present study investigates the roles of TIMP-1 on the EMT process and formation of the lumen-like structure in a 3D Matrigel culture of MDCK cells. We show that TIMP-1 overexpression effectively prevents cell polarization and acinar-like structure formation. TIMP-1 induces expression of the developmental EMT transcription factors such as SLUG, TWIST, ZEB1 and ZEB2, leading to downregulation of epithelial marker and upregulation of mesenchymal markers. Importantly, TIMP-1's ability to induce the EMT-like process is independent of its MMP-inhibitory domain. To our surprise, TIMP-1 induces migratory and invasive properties in MDCK cells. Here, we present a novel finding that TIMP-1 signaling upregulates MT1-MMP and MMP-2 expression, and potentiates MT1-MMP activation of pro-MMP-2, contributing to tumor cell invasion. In spite of the fact that TIMP-1, as opposed to TIMP-2, does not interact with and inhibit MT1-MMP, TIMP-1 may act as a key regulator of MT1-MMP/MMP-2 axis. Collectively, our findings suggest a model in which TIMP-1 functions as a signaling molecule and also as an endogenous inhibitor of MMPs. This concept represents a paradigm shift in the current view of TIMP-1/MT1-MMP interactions and functions during cancer development/progression.
- Subjects :
- Animals
Cell Line
Cell Movement physiology
Cell Polarity physiology
Cell Proliferation
DNA Primers genetics
Dogs
Flow Cytometry
Gene Knockdown Techniques
Immunoblotting
Matrix Metalloproteinase 14 metabolism
Matrix Metalloproteinase 2 metabolism
Reverse Transcriptase Polymerase Chain Reaction
Tetrazolium Salts
Thiazoles
Epithelial-Mesenchymal Transition physiology
Gene Expression Regulation physiology
Phenotype
Tissue Inhibitor of Metalloproteinase-1 metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 7
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 22701711
- Full Text :
- https://doi.org/10.1371/journal.pone.0038773