A Novel Function of Syndecan-2, Suppression of Matrix Metalloproteinase-2 Activation, Which Causes Suppression of Metastasis

The syndecans comprise a family of cell surface heparan sulfate proteoglycans exhibiting complex biological functions involving the interaction of heparan sulfate side chains with a variety of soluble and insoluble heparin-binding extracellular ligands. Here we demonstrate an inverse correlation between the expression level of syndecan-2 and the metastatic potential of three clones derived from Lewis lung carcinoma 3LL. This correlation was proved to be a causal relationship, because transfection of syndecan-2 into the higher metastatic clone resulted in the suppression of both spontaneous and experimental metastases to the lung. Although the expression levels of matrix metalloproteinase-2 (MMP-2) and its cell surface activators, such as membrane-type 1 matrix metalloproteinase and tissue inhibitor of metalloproteinase-2, were similar regardless of the metastatic potentials of the clones, elevated activation of MMP-2 was observed in the higher metastatic clone. Removal of heparan sulfate from the cell surface of low metastatic cells by treatment with heparitinase-I promoted MMP-2 activation, and transfection of syndecan-2 into highly metastatic cells suppressed MMP-2 activation. Furthermore, transfection of mutated syndecan-2 lacking glycosaminoglycan attachment sites into highly metastatic cells did not have any suppressive effect on MMP-2 activation, suggesting that this suppression was mediated by the heparan sulfate side chains of syndecan-2. Actually, MMP-2 was found to exhibit a strong binding ability to heparin, the dissociation constant value being 62 nm. These results indicate a novel function of syndecan-2, which acts as a suppressor for MMP-2 activation, causing suppression of metastasis in at least the metastatic system used in the present study.

Download Full-text

Faculty Opinions recommendation of Proteolysis of cell-surface tissue transglutaminase by matrix metalloproteinase-2 contributes to the adhesive defect and matrix abnormalities in thrombospondin-2-null fibroblasts and mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1028943.342441 ◽

2005 ◽

Author(s):

Helen Gruber

Keyword(s):

Cell Surface ◽

Matrix Metalloproteinase ◽

Tissue Transglutaminase ◽

Matrix Metalloproteinase 2

Download Full-text

Prognostic values of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 expression in bladder cancer

Cancer ◽

10.1002/(sici)1097-0142(19980401)82:7<1359::aid-cncr20>3.0.co;2-4 ◽

1998 ◽

Vol 82 (7) ◽

pp. 1359-1366 ◽

Cited By ~ 112

Author(s):

Hiro-omi Kanayama ◽

Kin-ya Yokota ◽

Yasushi Kurokawa ◽

Yoshihide Murakami ◽

Masaaki Nishitani ◽

...

Keyword(s):

Bladder Cancer ◽

Matrix Metalloproteinase ◽

Tissue Inhibitor Of Metalloproteinase ◽

Matrix Metalloproteinase 2 ◽

Tissue Inhibitor

Download Full-text

Higher Dialysate Matrix Metalloproteinase-2 Levels are Associated with Peritoneal Membrane Dysfunction

Peritoneal Dialysis International ◽

10.3747/pdi.2013.00274 ◽

2016 ◽

Vol 36 (1) ◽

pp. 16-25 ◽

Cited By ~ 4

Author(s):

Yeoungjee Cho ◽

David W. Johnson ◽

David A. Vesey ◽

Carmel M. Hawley ◽

Elaine M. Pascoe ◽

...

Keyword(s):

Matrix Metalloproteinase ◽

Primary Outcome ◽

Incidence Rate Ratio ◽

Tissue Inhibitor Of Metalloproteinase ◽

Matrix Metalloproteinase 2 ◽

Peritoneal Membrane ◽

Low Glucose ◽

Multilevel Linear Regression ◽

Peritoneal Solute Transport Rate ◽

Standard Solutions

♦ Background Peritoneal dialysis (PD) patients develop progressive and cumulative peritoneal injury with longer time spent on PD. The present study aimed to a) describe the trend of peritoneal injury biomarkers, matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinase-1 (TIMP-1), in incident PD patients, b) to explore the capacity of dialysate MMP-2 to predict peritoneal solute transport rate (PSTR) and peritonitis, and c) to evaluate the influence of neutral pH, low glucose degradation product (GDP) PD solution on these outcomes. ♦ Methods The study included 178 participants from the balANZ trial who had at least 1 stored dialysate sample. Changes in PSTR and peritonitis were primary outcome measures, and the utility of MMP-2 in predicting these outcomes was analyzed using multilevel linear regression and multilevel Poisson regression, respectively. ♦Results Significant linear increases in dialysate MMP-2 and TIMP-1 concentrations were observed ( p < 0.001), but neither was affected by the type of PD solutions received (MMP-2: p = 0.07; TIMP-1: p = 0.63). An increase in PSTR from baseline was associated with higher levels of MMP-2 ( p = 0.02), and the use of standard solutions over longer PD duration ( p = 0.001). The risk of peritonitis was independently predicted by higher dialysate MMP-2 levels (incidence rate ratio [IRR] per ng/mL 1.01, 95% confidence interval [CI] 1.005 – 1.02, p = 0.002) and use of standard solutions (Biocompatible solution: IRR 0.45, 95% CI 0.24 – 0.85, p = 0.01). ♦ Conclusion Dialysate MMP-2 and TIMP-1 concentrations increased with longer PD duration. Higher MMP-2 levels were associated with faster PSTR and future peritonitis risk. Administration of biocompatible solutions exerted no significant effect on dialysate levels of MMP-2 or TIMP-1, but did counteract the increase in PSTR and the risk of peritonitis associated with the use of standard PD solutions. This is the first longitudinal study to examine the clinical utility of MMP-2 as a predictor of patient-level outcomes.

Download Full-text