Identification of MMP-15 as an anti-apoptotic factor in cancer cells
Identification of MMP-15 as an anti-apoptotic factor in cancer cells
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DOI：
10.1074/jbc.m508155200
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发表时间：
2005-10-07
影响因子：
4.8
通讯作者：
Ullrich, A
中科院分区：
文献类型：
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作者：
Abraham, R;Schäfer, J;Ullrich, A
我们已经进行了体外选择的抗凋亡表型，类似于选择过程中，癌前细胞在体内癌变的初始阶段进行。使用宫颈癌细胞系HeLa S3作为模型系统，选择过程产生的细胞克隆显示增加的抵抗Fas，肿瘤坏死因子相关的凋亡诱导配体，和血清饥饿诱导的细胞凋亡。使用基因家族聚焦cDNA阵列的基因表达谱分析揭示了许多在HeLa S3和抗性亚克隆中差异表达的基因，因此可能参与对凋亡刺激的敏感性的定义。从这种功能基因组学方法中鉴定的基因中，我们通过小干扰RNA介导的敲减和亲代HeLa S3细胞中的异位表达验证了膜锚定基质金属蛋白酶15（MMP-15）的抗凋亡活性，并证实了我们的发现在其他癌细胞系中的更普遍意义。与正常肺相比，MMP-15在人肺腺癌中的过表达支持了这些发现的体内相关性。由于MMP-15是已知的，以促进入侵，我们的研究结果表明，这种蛋白酶连接转移和细胞凋亡抵抗的一个未知的调节机制。因此，我们的研究结果强烈表明，癌症特征，如转移潜力，这被认为是在癌症进展的后期演变，可以通过选择抗凋亡表型早期表现出来。
We have performed an in vitro selection for an anti-apoptotic phenotype that resembles the selection process that pre-malignant cells undergo in the initial phase of carcinogenesis in vivo. Using the cervical carcinoma cell line HeLa S3 as a model system, the selection procedure yielded cell clones that displayed increased resistance to apoptosis induced by Fas, tumor necrosis factor-related apoptosis-inducing ligand, and serum starvation. Gene expression profiling using gene family focused cDNA arrays revealed numerous genes that are differentially expressed in HeLa S3 and the resistant subclones and therefore are potentially involved in the definition of sensitivity to apoptotic stimuli. From the genes identified in this functional genomics approach we validated the anti-apoptotic activity of the membrane-anchored matrix metalloproteinase 15 (MMP-15) by means of small interfering RNA-mediated knockdown and ectopic expression in parental HeLa S3 cells and, to confirm a more general significance of our findings, in other cancer cell lines. The in vivo relevance of these findings is supported by the overexpression of MMP-15 in human lung adenocarcinoma compared with normal lung. Because MMP-15 is known to promote invasion, our results suggest that this protease connects metastasis and apoptosis resistance by an unknown regulatory mechanism. Our findings therefore strongly suggest that cancer characteristics such as metastatic potential, which are thought to evolve late in cancer progression, could be manifested early on by selection for an anti-apoptotic phenotype.