Matrilysin mediates extracellular cleavage of E-cadherin from prostate cancer cells: a key mechanism in hepatocyte growth factor/scatter factor-induced cell-cell dissociation and in vitro invasion.
OBJECTIVE
The current study examined the effects of hepatocyte growth factor/scatter factor (HGF/SF) on cell-cell dissociation, invasion, and its association with the mediated release of matrix metalloproteinase-7 (Matrilysin) on the extracellular cleavage of E-cadherin in prostate cancer cells.


METHODS
The effects of HGF/SF on cell-cell dissociation, in vitro invasion, and on the expression of E-cadherin at both protein and mRNA levels were assessed in cells whose expression of Matrilysin was altered by treatment with antisense oligonucleotide.


RESULTS
Incubation with HGF/SF mediated the release of active Matrilysin (M(r) 19,000), resulting in extracellular cleavage of E-cadherin from prostate cancer cells. This resultant soluble M(r) 80,000 fragment of E-cadherin was subsequently recognized upon immunoprobing with an anti-E-cadherin antibody. Both recombinant human Matrilysin (rh-Matrilysin) and/or HGF/SF increased the level of soluble E-cadherin and decreased the level of full-length (M(r) 120,000) E-cadherin as detected by Western blotting. The effects of rh-Matrilysin and HGF/SF were inhibited by an antisense oligonucleotide specifically directed toward human Matrilysin. In addition, stimulation with either rh-Matrilysin or HGF/SF resulted in disruption to the E-cadherin/beta-catenin complex, as shown by a significant increase (P < 0.05) in both cell scattering and invasion index.


CONCLUSIONS
Treatment with HGF/SF induced Matrilysin-mediated cleavage to the extracellular domain of E-cadherin, resulting in its dissociation from the cadherin/catenin complex. This provides a new mechanism in HGF/SF-induced cell scattering, resulting in a switch to a more invasive phenotype in LNCapFGC cells, as demonstrated by in vitro invasion.
Davies
G
G
Metastasis Research Group, University Department of Surgery, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK. daviesg11@cf.ac.uk
Jiang
W G
WG
Mason
M D
MD
D015820:Cadherins / Q000187:drug effects / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000737:chemistry; D003598:Cytoskeletal Proteins / Q000187:drug effects / Q000378:metabolism; D016373:DNA, Antisense / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008297:Male; D020783:Matrix Metalloproteinase 7 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008934:Mitogens / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D011092:Polyethylene Glycols; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility; D013347:Subcellular Fractions; D013997:Time Factors; D015534:Trans-Activators; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; D016373:DNA, Antisense; D008934:Mitogens; D011994:Recombinant Proteins; D015534:Trans-Activators; D051176:beta Catenin; D011092:Polyethylene Glycols; D017228:Hepatocyte Growth Factor; D020783:Matrix Metalloproteinase 7