Cellular and Molecular Medicine Programme, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
Blood. 2010 Jan 28;115(4):846-9. doi: 10.1182/blood-2009-08-239426. Epub 2009 Nov 19.
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.
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 (MMP-9) 和血管内皮生长因子 (VEGF)。我们研究了 VEGF 是否调节 MMP-9。VEGF 通过明胶酶谱法以剂量依赖性方式显著降低 MMP-9 蛋白表达。阻断 VEGFR2 受体恢复了 MMP-9 水平，表明该受体参与了观察到的效应。VEGF 下调 MMP-9 导致 B-CLL 细胞通过 Matrigel 或人脐静脉内皮细胞的迁移显著抑制，证实了 MMP-9 在这些过程中的关键作用。逆转录聚合酶链反应分析显示，VEGF 在转录水平上调节 MMP-9。事实上，VEGF 诱导 STAT1 酪氨酸磷酸化，而 VEGFR2 的抑制阻断了这一作用。STAT1 负责 MMP-9 的下调，因为 STAT1 基因沉默在 VEGF 存在的情况下恢复了 MMP-9 的产生和 B-CLL 细胞的迁移。因此，VEGF 和 MMP-9 的水平影响 B-CLL 细胞的扩增，这两种分子都可能成为该疾病的治疗靶点。
