The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase
The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase
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DOI：
10.1093/carcin/bgi183
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发表时间：
2005-12-01
期刊：
影响因子：
4.7
通讯作者：
Yong, VW
中科院分区：
文献类型：
--
作者：
Zhang, J;Sarkar, S;Yong, VW
已经发现趋化因子改变肿瘤生长和转移。我们先前已经描述了一种特定的趋化因子受体CXCR 4主要在各种胶质瘤细胞系和切除的胶质母细胞瘤标本中表达。在此，我们已经测试了CXCR 4的配体，基质细胞衍生因子-1 α（SDF-1 α，CXCL 12）对人神经胶质瘤细胞的反应。我们发现SDF-1 α增加了膜型2型基质金属蛋白酶（MT 2-MMP）的表达，但不增加其他MT-MMPs、MMP-2或MMP-9的表达。SDF-1 α增强的MT 2-MMP表达被CXCR 4拮抗剂AMD 3100阻断。功能性侵袭实验表明，SDF-1 α刺激胶质瘤细胞通过基质胶包被的小室侵袭，并且这种作用在胶质瘤细胞中通过使用小干扰RNA（siRNA）稳定下调MT 2-MMP表达而被抑制。在体内和在脑内植入细胞后的无症状阶段，与植入非特异性siRNA对照细胞的小鼠相比，携带MT 2-MMP siRNA下调克隆的小鼠具有更小且侵袭性更低的肿瘤。在症状阶段的分析表明，具有MT 2-MMP siRNA克隆的小鼠比携带对照细胞的小鼠存活更长时间。这些结果突出了MT 2-MMP作为胶质瘤细胞中CXCR 4信号传导的效应物，并且它们揭示了MT 2-MMP在调节肿瘤活性中的新作用。
Chemokines have been found to alter tumor growth and metastasis. We have described previously that a particular chemokine receptor, CXCR4, was predominantly expressed on various glioma cell lines and in resected glioblastoma specimens. Herein, we have tested the ligand of CXCR4, stromal cell derived factor-1 alpha (SDF-1 alpha, CXCL12), on the response of human glioma cells. We found that SDF-1 alpha increased the expression of membrane type-2 matrix metalloproteinase (MT2-MMP), but not the other MT-MMPs, MMP-2 or MMP-9. The SDF-1 alpha enhanced MT2-MMP expression was blocked by a CXCR4 antagonist, AMD3100. Functional invasion assays showed that SDF-1 alpha stimulated glioma cells to invade through matrigel-coated chambers and this effect was inhibited in glioma cells by the stable downregulation of MT2-MMP expression using small interfering RNA (siRNA). In vivo and at asymptomatic stages following intracerebral implant of cells, mice harboring MT2-MMP siRNA downregulated clones had smaller and less invasive tumors compared with mice implanted with non-specific siRNA control cells. Analyses at symptomatic stages demonstrate that mice with MT2-MMP siRNA clones survive longer than mice harboring control cells. These results highlight MT2-MMP as an effector of CXCR4 signaling in glioma cells, and they reveal the novel role of MT2-MMP in modulating tumor activity.