Matrix Metalloproteinase-13 (MMP-13) Directly and Indirectly Promotes Tumor Angiogenesis
Matrix Metalloproteinase-13 (MMP-13) Directly and Indirectly Promotes Tumor Angiogenesis
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DOI：
10.1074/jbc.m112.373159
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发表时间：
2012-11-09
影响因子：
4.8
通讯作者：
Takata, Takashi
中科院分区：
文献类型：
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作者：
Kudo, Yasusei;Iizuka, Shinji;Takata, Takashi
基质金属蛋白酶（Matrix metalloproteinases，MMPs）是一类锌离子依赖的细胞外内肽酶，参与细胞外基质的降解和重塑。MMP还在细胞增殖、迁移、分化、血管生成和凋亡中起作用。我们先前通过比较亲本和高侵袭性癌细胞克隆之间的基因表达谱来确定癌症侵袭相关因素。基质金属蛋白酶-13（MMP-13）是肿瘤侵袭相关因子共同上调表达的基因。虽然MMP-13轻微促进肿瘤侵袭，但我们发现MMP-13参与肿瘤血管生成。MMP-13过表达细胞的条件培养基促进永生化人脐静脉内皮细胞毛细血管形成。此外，用重组MMP-13蛋白治疗增强了体外和体内的毛细血管形成。MMP-13促进毛细血管形成是通过激活黏着斑激酶和ERK介导的。有趣的是，MMP-13促进成纤维细胞和内皮细胞分泌VEGF-A。通过免疫组化分析，我们发现MMP-13的表达与人类癌症病例中血管的数量之间可能存在相关性。总之，这些发现表明MMP-13可能直接和间接促进肿瘤血管生成。
Matrix metalloproteinases (MMPs) are extracellular zinc-dependent endopeptidases involved in the degradation and remodeling of extracellular matrix in physiological and pathological processes. MMPs also have a role in cell proliferation, migration, differentiation, angiogenesis, and apoptosis. We previously identified cancer invasion-related factors by comparing the gene expression profiles between parent and the highly invasive clone of cancer cells. Matrix metalloproteinase-13 (MMP-13) was identified as a common up-regulated gene by cancer invasion-related factors. Although MMP-13 slightly promoted tumor invasion, we found that MMP-13 was involved in tumor angiogenesis. Conditioned medium from MMP-13-overexpressing cells promoted capillary formation of immortalized human umbilical vein endothelial cells. Furthermore, treatment with recombinant MMP-13 protein enhanced capillary tube formation both in vitro and in vivo. MMP-13-promoted capillary tube formation was mediated by activation of focal adhesion kinase and ERK. Interestingly, MMP-13-promoted the secretion of VEGF-A from fibroblasts and endothelial cells. By immunohistochemical analysis, we found a possible correlation between MMP-13 expression and the number of blood vessels in human cancer cases. In summary, these findings suggest that MMP-13 may directly and indirectly promote tumor angiogenesis.