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Study on novel functions of membrane-type matrix metalloproteinase in tumor metastasis

膜型基质金属蛋白酶在肿瘤转移中的新功能研究

基本信息

批准号：
14370053
负责人：
SATO Hiroshi
金额：
$ 8.77万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370053/
关键词：
MT1-MMP Testican N-Tes KiSS-1 Mtastasis Syndecan Lumican Collagen 細胞外マトリックス細胞運動 metastin GPCR HT-1080

项目摘要

Membrane-type matrix metalloproteinase(MT1-MMP) is expressed on the surface of tumor cells, and thought to play an important role in tumor invasion and metastasis. However, the functions of MT1-MMP still remain unsolved, and would not be investigated by classical biochemical approach. We have developed a novel expression cloning method to screen molecules, which either regulate MT1-MMP activity or serve as substrates for it, and identified several molecules. For example, syndecan-1, expression of which is known to have reverse co-relation with the malignancy of tumors, was demonstrated to be cleaved to shed the ecto-domain. Expression of syndecan-1 was shown to suppress cell migration on collagen, which was abrogated by the cleavage of syndecan-1 by MT1-MMP. Furthermore, we identified metastasis suppressor gene product KiSS-1 protein as a substrate for MMP. Metastin peptide encoded by KiSS-1 gene was also shown to be cleaved by MMP. Metastin is known to repress cell migration by binding to the G-protein-coupled receptor(GPCR). Since metastin is inactivated by MMPs produced by tumor cells, migration of tumor cells expressing GPCR could be suppressed by co-treatment with metastin and MMP inhibitor. These results suggest that study on functions of MT1-MMP may contribute to the development of novel therapy targeting MT1-MMP.

膜型基质金属蛋白酶（MT1-MMP）表达于肿瘤细胞表面，被认为在肿瘤侵袭和转移中发挥重要作用。然而，MT1-MMP的功能仍然没有得到解决，并且不会通过经典的生化方法进行研究。我们开发了一种新的表达克隆方法来筛选调节 MT1-MMP 活性或作为其底物的分子，并鉴定了几种分子。例如，syndecan-1 的表达已知与肿瘤的恶性程度具有反向相关性，已被证明被切割以释放胞外域。 syndecan-1 的表达可抑制胶原蛋白上的细胞迁移，而 MT1-MMP 裂解 syndecan-1 可以消除这种现象。此外，我们鉴定了转移抑制基因产物KiSS-1蛋白作为MMP的底物。 KiSS-1 基因编码的肿瘤转移蛋白肽也被证明可以被 MMP 切割。众所周知，Metastin 通过与 G 蛋白偶联受体 (GPCR) 结合来抑制细胞迁移。由于转移蛋白被肿瘤细胞产生的 MMP 灭活，因此表达 GPCR 的肿瘤细胞的迁移可以通过转移蛋白和 MMP 抑制剂的共同治疗来抑制。这些结果表明，对MT1-MMP功能的研究可能有助于开发针对MT1-MMP的新疗法。