Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth
Transcription factor Egr-1 supports FGF-dependent angiogenesis during neovascularization and tumor growth
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DOI：
10.1038/nm905
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发表时间：
2003-08-01
期刊：
影响因子：
82.9
通讯作者：
Khachigian, LM
中科院分区：
文献类型：
--
作者：
Fahmy, RG;Dass, CR;Khachigian, LM
目前对调节血管生成的关键转录因子的了解有限。在这里，我们发现rna切割磷酸二酯连接dna的酶（DNAzymes），靶向早期生长反应（Egr-1） mRNA的5个非翻译区域的特定基序，抑制Egr-1蛋白的表达，微血管内皮细胞的复制和迁移，以及基膜基质上微管网络的形成。Egr-1 DNAzymes阻断小鼠皮下Matrigel栓子中的血管生成，这一观察结果在Egr-1缺陷动物的栓子分析中得到了独立证实，并且在裸鼠中抑制MCF-7人乳腺癌的生长。Egr-1 DNAzymes抑制肿瘤生长，但不影响体重、伤口愈合、凝血或其他血液学参数。这些药物抑制成纤维细胞生长因子(FGF)-2 （Egr-1下游的促血管生成因子）的内皮表达，但不抑制血管内皮生长因子（VEGF）。Egr-1 DNAzymes也抑制大鼠角膜新生血管的形成。因此，微血管内皮细胞生长、新生血管形成、肿瘤血管生成和肿瘤生长都是严重依赖于Egr-1的过程。
Current understanding of key transcription factors regulating angiogenesis is limited. Here we show that RNA-cleaving phosphodiester- linked DNA-based enzymes (DNAzymes), targeting a specific motif in the 5 untranslated region of early growth response (Egr-1) mRNA, inhibit Egr-1 protein expression, microvascular endothelial cell replication and migration, and microtubule network formation on basement membrane matrices. Egr-1 DNAzymes blocked angiogenesis in subcutaneous Matrigel plugs in mice, an observation that was independently confirmed by plug analysis in Egr-1-deficient animals, and inhibited MCF-7 human breast carcinoma growth in nude mice. Egr-1 DNAzymes suppressed tumor growth without influencing body weight, wound healing, blood coagulation or other hematological parameters. These agents inhibited endothelial expression of fibroblast growth factor (FGF)-2, a proangiogenic factor downstream of Egr-1, but not that of vascular endothelial growth factor (VEGF). Egr-1 DNAzymes also repressed neovascularization of rat cornea. Thus, microvascular endothelial cell growth, neovascularization, tumor angiogenesis and tumor growth are processes that are critically dependent on Egr-1.