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.
Munesue
Seiichi
S
Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Kyoto 603-8555, Japan.
Yoshitomi
Yasuo
Y
Kusano
Yuri
Y
Koyama
Yoshie
Y
Nishiyama
Akiko
A
Nakanishi
Hayao
H
Miyazaki
Kaoru
K
Ishimaru
Takeshi
T
Miyaura
Shuichi
S
Okayama
Minoru
M
Oguri
Kayoko
K
D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006493:Heparin / Q000737:chemistry; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009362:Neoplasm Metastasis; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D053669:Syndecan-2 / Q000378:metabolism / Q000502:physiology*; D013997:Time Factors; D014162:Transfection
D053669:Syndecan-2; D006493:Heparin; D020778:Matrix Metalloproteinase 2