Membrane type 1 matrix metalloproteinase induces epithelial-to-mesenchymal transition in prostate cancer.
By mining DNA microarray data bases at GenBank, we identified up-regulation of membrane type 1 matrix metalloproteinase (MT1-MMP) in human primary and metastatic prostate cancer specimens as compared with nonmalignant prostate tissues. To explore the role of up-regulated MT1-MMP in early stage cancer progression, we have employed a three-dimensional cell culture model. Minimally invasive human prostate cancer cells (LNCaP) were transfected with MT1-green fluorescent protein (GFP) chimeric cDNA as compared with GFP cDNA, and morphologic and phenotypic changes were characterized. GFP-expressing LNCaP cells formed multicellular spheroids with cuboidal-like epithelial morphology, whereas MT1-GFP-expressing cells displayed a fibroblast-like morphology and a scattered growth pattern in type I collagen gels. Cell morphologic changes were accompanied by decreased epithelial markers and enhanced mesenchymal markers, consistent with epithelial-to-mesenchymal transition. MT1-MMP-induced morphologic change and cell scattering were abrogated by target inhibition of either the catalytic domain or the hemopexin domain. We further demonstrated that MT1-MMP-induced phenotypic changes were dependent upon up-regulation of Wnt5a, which has been implicated in epithelial-to-mesenchymal transition. We conclude that MT1-MMP plays an important role in early cancer dissemination by converting epithelial cells to migratory mesenchymal-like cells.
Cao
Jian
J
Department of Medicine, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA. jian.cao@sunysb.edu
Chiarelli
Christian
C
Richman
Omer
O
Zarrabi
Kevin
K
Kozarekar
Pallavi
P
Zucker
Stanley
S
D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis* / Q000235:genetics; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D018874:Spheroids, Cellular / Q000201:enzymology / Q000473:pathology; D051153:Wnt Proteins / Q000096:biosynthesis / Q000235:genetics; D000071818:Wnt-5a Protein
D011518:Proto-Oncogene Proteins; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1