Decorin Antagonizes the Angiogenic Network CONCURRENT INHIBITION OF MET, HYPOXIA INDUCIBLE FACTOR 1α, VASCULAR ENDOTHELIAL GROWTH FACTOR A, AND INDUCTION OF THROMBOSPONDIN-1 AND TIMP3
Decorin Antagonizes the Angiogenic Network CONCURRENT INHIBITION OF MET, HYPOXIA INDUCIBLE FACTOR 1α, VASCULAR ENDOTHELIAL GROWTH FACTOR A, AND INDUCTION OF THROMBOSPONDIN-1 AND TIMP3
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DOI：
10.1074/jbc.m111.283499
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发表时间：
2012-02-17
影响因子：
4.8
通讯作者：
Iozzo, Renato V.
中科院分区：
文献类型：
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作者：
Neill, Thomas;Painter, Hannah;Iozzo, Renato V.
核心蛋白聚糖是一种富含亮氨酸的小分子蛋白聚糖，通过拮抗EGFR和Met等多种受体酪氨酸激酶抑制肿瘤生长。在这里，我们研究了在常氧血管生成信号的核心蛋白聚糖。血管生成PCR阵列揭示了深刻的核心蛋白聚糖诱发的促血管生成基因，如HIF 1A的转录抑制。核心蛋白聚糖引起表达组成型活性HIF-1 α的MDA-231乳腺癌细胞中缺氧诱导因子（HIF）-1 α和血管内皮生长因子A（VEGFA）的减少。用核心蛋白聚糖或siRNA抑制Met通过减弱下游β-连环蛋白信号传导引起VEGFA的类似减少。这些数据确立了β-连环蛋白在调节VEGFA表达中的非经典作用。我们发现，外源性核心蛋白聚糖诱导血小板反应蛋白-1和TIMP 3，两个强大的血管抑制剂的表达。相比之下，核心蛋白聚糖抑制基质金属蛋白酶（MMP）-9和MMP-2，两个促血管生成蛋白酶的表达和酶活性。我们的数据建立了一个新的双重性核心蛋白聚糖作为肿瘤血管生成的抑制剂在常氧下，同时下调有效的促血管生成因子和诱导内源性抗血管生成剂。
Decorin, a small leucine-rich proteoglycan, inhibits tumor growth by antagonizing multiple receptor tyrosine kinases including EGFR and Met. Here, we investigated decorin during normoxic angiogenic signaling. An angiogenic PCR array revealed a profound decorin-evoked transcriptional inhibition of pro-angiogenic genes, such as HIF1A. Decorin evoked a reduction of hypoxia inducible factor (HIF)-1 alpha and vascular endothelial growth factor A (VEGFA) in MDA-231 breast carcinoma cells expressing constitutively-active HIF-1 alpha. Suppression of Met with decorin or siRNA evoked a similar reduction of VEGFA by attenuating downstream beta-catenin signaling. These data establish a noncanonical role for beta-catenin in regulating VEGFA expression. We found that exogenous decorin induced expression of thrombospondin-1 and TIMP3, two powerful angiostatic agents. In contrast, decorin suppressed both the expression and enzymatic activity of matrix metalloprotease (MMP)-9 and MMP-2, two pro-angiogenic proteases. Our data establish a novel duality for decorin as a suppressor of tumor angiogenesis under normoxia by simultaneously down-regulating potent pro-angiogenic factors and inducing endogenous anti-angiogenic agents.