Noël A, Boulay A, Kebers F, Kannan R, Hajitou A, Calberg-Bacq C M, Basset P, Rio M C, Foidart J M
Laboratory of Tumor and Developmental Biology, University of Liège, 4000 Sart-Tilman, Liège, Belgium.
Oncogene. 2000 Mar 16;19(12):1605-12. doi: 10.1038/sj.onc.1203465.
Stromelysin-3 (ST3), a matrix metalloproteinase (MMP) expressed in aggressive carcinomas, has been shown to promote tumor development in different in vivo experimental models. However, the inability of its mature form to degrade extracellular matrix components casts doubt on whether ST3 functions in vivo as a protease. In this study, we evaluated whether the ST3 tumor-promoting effect could be ascribed to its proteolytic activity and whether this putative protease could be targeted with MMP inhibitors. Catalytically inactive mutant cDNA of human (h) ST3 or mouse (m) ST3 were generated and transfected into MCF7 cells. When injected into nude mice in the presence of matrigel, the mutant-bearing cells did not exhibit the enhanced tumorigenicity elicited by MCF7 cells transfected with wild-type ST3 cDNA. In a second approach, TIMP2 overproduction in MCF7 cells expressing hST3 was induced by retroviral infection. The co-expression of ST3 and TIMP2 failed to enhance the tumorigenicity of MCF7 cells. Notably, matrigel depleted of low-molecular-weight proteins and growth factors failed to promote the tumorigenicity of ST3-expressing MCF7 cells. These findings provide the first in vivo evidence that ST3 is indeed a protease that can modulate cancer progression by remodeling extracellular matrix and probably by inducing it to release the necessary microenvironmental factors. Thus, ST3 represents an interesting target for specific MMP inhibition.
基质溶解素-3（ST3）是一种在侵袭性癌中表达的基质金属蛋白酶（MMP），在不同的体内实验模型中已显示其可促进肿瘤发展。然而，其成熟形式无法降解细胞外基质成分，这让人怀疑ST3在体内是否作为一种蛋白酶发挥作用。在本研究中，我们评估了ST3的促肿瘤作用是否可归因于其蛋白水解活性，以及这种假定的蛋白酶是否可用MMP抑制剂靶向。构建了人（h）ST3或小鼠（m）ST3的催化失活突变体cDNA，并将其转染到MCF7细胞中。当在基质胶存在的情况下注射到裸鼠体内时，携带突变体的细胞并未表现出由野生型ST3 cDNA转染的MCF7细胞所引发的增强的致瘤性。在第二种方法中，通过逆转录病毒感染诱导表达hST3的MCF7细胞中TIMP2的过量产生。ST3和TIMP2的共表达未能增强MCF7细胞的致瘤性。值得注意的是，去除了低分子量蛋白质和生长因子的基质胶未能促进表达ST3的MCF7细胞的致瘤性。这些发现提供了首个体内证据，表明ST3确实是一种蛋白酶，它可以通过重塑细胞外基质并可能通过诱导其释放必要的微环境因子来调节癌症进展。因此，ST3是特异性MMP抑制的一个有趣靶点。
