Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5
Regulation of angiogenesis through a microRNA (miR-130a) that down-regulates antiangiogenic homeobox genes GAX and HOXA5
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DOI：
10.1182/blood-2007-07-104133
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发表时间：
2008-02-01
期刊：
影响因子：
20.3
通讯作者：
Gorski, David H.
中科院分区：
文献类型：
--
作者：
Chen, Yun;Gorski, David H.
血管生成对肿瘤进展至关重要。同源异型盒基因GAX抑制血管内皮细胞（EC）中的血管生成。我们已经确定了一个microRNA（miR-130 a），调节GAX的表达，并假设它在调节GAX的活性在EC中起着重要作用。来自GAX X非翻译区（3 '-UTR）的280 bp片段含有2个miR-130 a靶向位点，观察到血清和促血管生成因子快速下调GAX表达所需，而GAX启动子的活性不随血清或促血管生成因子的暴露而变化。GAX 3 '-UTR中的这一相同的280 bp序列克隆到psiphylK 2-荧光素酶载体中，当置于报告基因的3'端时，介导了血清诱导的报告基因的下调。最后，miR-130 a的强制表达通过这一特异性GAX 3 '-UTR序列抑制GAX表达。对其他可能的miR-130 a结合位点的全基因组搜索揭示了抗血管生成同源框基因HOXA 5的3 '-UTR中的miR-130 a靶向位点，其表达和抗血管生成活性也被miR-130 a抑制。从这些数据中，我们得出结论，miR-130 a是血管内皮细胞血管生成表型的调节剂，主要是通过其调节GAX和HOXA 5表达的能力。
Angiogenesis is critical to tumor progression. The homeobox gene GAX inhibits angiogenesis in vascular endothelial cells (ECs). We have identified a microRNA (miR-130a) that regulates GAX expression and hypothesized that it plays a major role in modulating GAX activity in ECs. A 280-bp fragment from the GAX X-untranslated region (3'-UTR) containing 2 miR-130a targeting sites was observed to be required for the rapid down-regulation of GAX expression by serum and proangiogenic factors, whereas the activity of the GAX promoter did not vary with exposure to serum or proangiogenic factors. This same 280-bp sequence in the GAX 3'-UTR cloned into the psiCHECK2-Luciferase vector mediated serum-induced down-regulation of the reporter gene when placed 3' of it. Finally, forced expression of miR-130a inhibits GAX expression through this specific GAX 3'-UTR sequence. A genome-wide search for other possible miR-130a binding sites revealed an miR-130a targeting site in the 3'-UTR of the antiangiogenic homeobox gene HOXA5, the expression and antiangiogenic activity of which are also inhibited by miR-130a. From these data, we conclude that miR-130a is a regulator of the angiogenic phenotype of vascular ECs largely through its ability to modulate the expression of GAX and HOXA5.