VEGF/VEGFR2 interaction down-regulates matrix metalloproteinase-9 via STAT1 activation and inhibits B chronic lymphocytic leukemia cell migration.
VEGF/VEGFR2 interaction down-regulates matrix metalloproteinase-9 via STAT1 activation and inhibits B chronic lymphocytic leukemia cell migration.
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VEGF/VEGFR2 相互作用通过 STAT1 激活下调基质金属蛋白酶-9，并抑制 B 慢性淋巴细胞白血病细胞迁移。
DOI：
10.1182/blood-2009-08-239426
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发表时间：
2010
期刊：
影响因子：
20.3
通讯作者：
A. García
中科院分区：
文献类型：
--
作者：
E. Ugarte;Javier Redondo;P. Eroles;Mercedes Hernández del Cerro;J. García;M. Terol;A. García
B细胞慢性淋巴细胞白血病(B-CLL)的迁移涉及多种分子，包括基质金属蛋白酶-9(MMP9)和血管内皮生长因子(VEGF)。我们已经研究了血管内皮生长因子是否调节基质金属蛋白酶-9。明胶酶谱显示，血管内皮细胞生长因子显著降低基质金属蛋白酶-9蛋白的表达，并呈剂量依赖关系。阻断VEGFR2受体可恢复基质金属蛋白酶-9水平，暗示该受体参与了观察到的效应。血管内皮生长因子下调基质金属蛋白酶-9可显著抑制B-CLL细胞通过Matrigel或人脐静脉内皮细胞的迁移，证实了基质金属蛋白酶-9在这一过程中的重要作用。逆转录聚合酶链式反应分析表明，血管内皮细胞生长因子在转录水平调控基质金属蛋白酶-9。事实上，血管内皮生长因子诱导STAT1酪氨酸磷酸化，并通过抑制血管内皮生长因子R2而被阻断。STAT1负责下调MMP9的表达，因为STAT1基因沉默恢复了MMP9的产生和B-CLL细胞在血管内皮生长因子存在下的迁移。因此，血管内皮生长因子和基质金属蛋白酶-9的水平影响B-CLL细胞的增殖，这两个分子可以成为治疗该疾病的靶点。
B-cell chronic lymphocytic leukemia (B-CLL) migration involves several molecules, including matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF). We have studied whether VEGF regulates MMP-9. VEGF significantly reduced MMP-9 protein expression in a dose-dependent manner, measured by gelatin zymography. Blocking the VEGFR2 receptor restored MMP-9 levels, implicating this receptor in the observed effect. Down-regulation of MMP-9 by VEGF resulted in significant inhibition of B-CLL cell migration through Matrigel or human umbilical vein endothelial cells, confirming the crucial role of MMP-9 in these processes. Reverse-transcription polymerase chain reaction analyses revealed that VEGF regulated MMP-9 at the transcriptional level. Indeed, VEGF induced STAT1 tyrosine phosphorylation, and this was blocked by inhibiting VEGFR2. STAT1 was responsible for MMP-9 down-regulation, as STAT1 gene silencing restored MMP-9 production and B-CLL cell migration in the presence of VEGF. Thus, the levels of VEGF and MMP-9 influence B-CLL cell expansion and both molecules could constitute therapeutic targets for this disease.
影响因子：
4.4
作者：
Z. Ma;H. Qin;E. Benveniste
通讯作者：
Z. Ma;H. Qin;E. Benveniste