Cancer Research UK Viral Oncology Group, UCL Cancer Institute, University College London, London, United Kingdom.
Blood. 2012 Dec 13;120(25):5063-72. doi: 10.1182/blood-2012-04-423004. Epub 2012 Oct 18.
Delta-like 4 (DLL4), a membrane-bound ligand belonging to the Notch signaling family, plays a fundamental role in vascular development and angiogenesis. We identified a conserved microRNA family, miR-30, which targets DLL4. Overexpression of miR-30b in endothelial cells led to increased vessel number and length in an in vitro model of sprouting angiogenesis. Microinjection of miR-30 mimics into zebrafish embryos resulted in suppression of dll4 and subsequent excessive sprouting of intersegmental vessels and reduction in dorsal aorta diameter. Use of a target protector against the miR-30 site within the dll4 3'UTR up-regulated dll4 and synergized with Vegfa signaling knockdown to inhibit angiogenesis. Furthermore, restoration of miR-30b or miR-30c expression during Kaposi sarcoma herpesvirus (KSHV) infection attenuated viral induction of DLL4. Together these results demonstrate that the highly conserved molecular targeting of DLL4 by the miR-30 family regulates angiogenesis.
Delta-like 4（DLL4）是 Notch 信号家族的一种膜结合配体，在血管发育和血管生成中起着重要作用。我们发现了一个保守的 microRNA 家族 miR-30，它靶向 DLL4。在体外发芽血管生成模型中，内皮细胞中 miR-30b 的过表达导致血管数量和长度增加。将 miR-30 模拟物微注射到斑马鱼胚胎中会导致 dll4 被抑制，随后节间血管过度发芽，背主动脉直径减小。使用针对 dll4 3'UTR 中 miR-30 位点的靶标保护物上调 dll4，并与 Vegfa 信号敲低协同抑制血管生成。此外，在卡波西肉瘤疱疹病毒（KSHV）感染期间恢复 miR-30b 或 miR-30c 的表达会减弱 DLL4 的病毒诱导。这些结果表明，miR-30 家族对 DLL4 的高度保守的分子靶向调节血管生成。
