Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function
Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function
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DOI：
10.1158/0008-5472.can-05-1208
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发表时间：
2005-10-01
期刊：
影响因子：
11.2
通讯作者：
Harris, AL
中科院分区：
文献类型：
--
作者：
Patel, NS;Li, JL;Harris, AL
Notch信号通路和Delta样4配体(DLL4)在胚胎血管发育中起关键作用。许多参与胚胎血管发育的通路在肿瘤血管生成中也起着重要作用。在这项研究中，我们评估了DLL4在原发性肾癌中的表达，并研究了DLL4在原代内皮细胞中的生物学功能。应用实时荧光定量聚合酶链式反应和原位杂交技术，我们发现DLL4在肾透明细胞癌血管内的表达上调，几乎是正常肾组织的9倍，并且与血管内皮生长因子(VEGF)的表达呈正相关。血管内皮生长因子和碱性成纤维细胞生长因子协同上调血管内皮细胞DLL4的表达，缺氧通过缺氧诱导因子Lα上调血管内皮细胞DLL4的表达。通过RNA干扰下调DLL4的表达，导致HEY1和EPhinB2的表达下降，抑制内皮细胞的增殖、迁移和网络形成，这些都是肿瘤血管生成的重要过程。在G(0)-G(1)细胞中，p21的表达增加，而视网膜母细胞瘤的磷酸化水平降低，细胞周期停滞，从而抑制细胞增殖。我们的结论是，DLL4表达的最佳窗口对于肿瘤血管生成是必不可少的，在人类肿瘤中选择性地调节DLL4表达可能代表一种潜在的抗血管生成治疗。
The Notch signaling pathway and the delta-like 4 ligand (DLL4) play key roles in embryonic vascular development. Many of the pathways involved in embryonic vascular development also play important roles in tumor angiogenesis. In this study, we assessed the expression of DLL4 in primary renal cancer and investigated the biological function of DLL4 in primary endothelial cells. Using real-time quantitative PCR and in situ hybridization, we showed that the expression of DLL4 was upregulated within the vasculature of clear cell-renal cell carcinoma almost 9-fold more than normal kidney and was correlated with the expression of vascular endothelial growth factor (VEGF). The expression of DLL4 in endothelial cells was up-regulated by VEGF and basic fibroblast growth factor synergistically, and by hypoxia through hypoxia-inducible factor l alpha. Down-regulation of DLL4 expression with RNA interference led to decreased expression of HEY1 and EphrinB2, and the inhibition of endothelial cell proliferation, migration, and network formation, all of which are important processes in tumor angiogenesis. The inhibition of proliferation occurred via the induction of cell cycle arrest in G(0)-G(1) by increased expression of p21 and decreased phosphorylation of retinoblastoma. We conclude that an optimal window of the DLL4 expression is essential for tumor angiogenesis and that selective modulation of the DLL4 expression within human tumors may represent a potential novel antiangiogenic therapy.