miRNA302-367-Erk1/2-Klf2-S1pr1 通路通过限制血管生成和改善血管稳定性来预防肿瘤生长。
A MicroRNA302-367-Erk1/2-Klf2-S1pr1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Improving Vascular Stability.
机构信息
From the Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, China (J.P., T.Z., H.S., X.C., J.L., Z.Y., L.Z., Y.Z.); Department of Geriatrics, Ruijin Hospital, School of Medicine (T.T.) and State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, School of Biomedical Engineering, (Y.S., X.W.), Shanghai Jiao Tong University, China; Institute for Biomedical Engineering and Nano Science, Tongji University School of Medicine, Shanghai, China (Y.C.); Med-X-Renji Hospital Stem Cell Research Center, Jiao Tong University School of Medicine, Shanghai, China (H.H.Z., W.-Q.G.); Division of Cardiology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taiwan (P.C.); Laboratory of Cardiovascular Signaling, Centenary Institute, Camperdown, New South Wales, Australia (X.Z.); Department of Medicine, Sydney Medical School, University of Sydney, New South Wales, Australia (X.Z.); Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA (Y.T.); and Department of Cell and Developmental Biology, Department of Medicine, Penn Cardiovascular Institute, Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia (E.M.).
出版信息
Circ Res. 2017 Jan 6;120(1):85-98. doi: 10.1161/CIRCRESAHA.116.309757. Epub 2016 Oct 18.
RATIONALE
Angiogenic hypersprouting and leaky vessels are essential for tumor growth. MicroRNAs have unique therapeutic advantages by targeting multiple pathways of tumor-associated angiogenesis, but the function of individual miRNAs of miR302-367 cluster in angiogenesis and tumors has not yet been fully evaluated.
OBJECTIVE
To investigate the functions of miR302-367 in developmental angiogenesis and tumor angiogenesis and explore the molecular mechanisms of microRNA for the treatment of pathological neovascularization-related diseases.
METHODS AND RESULTS
Here, we show that miR302-367 elevation in endothelial cells reduces retinal sprouting angiogenesis and promotes vascular stability in vivo, ex vivo, and in vitro. Erk1/2 is identified as direct target of miR302-367, and downregulation of Erk1/2 on miR302-367 elevation in endothelial cells increases the expression of Klf2 and in turn S1pr1 and its downstream target VE-cadherin, suppressing angiogenesis and improving vascular stability. Conversely, both pharmacological blockade and genetic deletion of S1pr1 in endothelial cells reverse the antiangiogenic and vascular stabilizing effect of miR302-367 in mice. Tumor angiogenesis shares features of developmental angiogenesis, and endothelial specific elevation of miR302-367 reduces tumor growth by restricting sprout angiogenesis and decreasing vascular permeability via the same Erk1/2-Klf2-S1pr1 pathways.
CONCLUSIONS
MiR302-367 regulation of an Erk1/2-Klf2-S1pr1 pathway in the endothelium advances our understanding of angiogenesis, meanwhile also provides opportunities for therapeutic intervention of tumor growth.
背景
血管生成过度发芽和渗漏血管对于肿瘤生长是必不可少的。microRNAs 通过靶向与肿瘤相关的血管生成的多个途径具有独特的治疗优势，但 miR302-367 簇中单个 miRNA 在血管生成和肿瘤中的功能尚未得到充分评估。
目的
研究 miR302-367 在发育性血管生成和肿瘤血管生成中的功能，并探讨 microRNA 治疗与病理性新生血管相关疾病的分子机制。
方法和结果
在这里，我们表明内皮细胞中 miR302-367 的升高可减少视网膜发芽血管生成，并在体内、体外和体外促进血管稳定性。Erk1/2 被鉴定为 miR302-367 的直接靶标，内皮细胞中 miR302-367 的下调增加了 Klf2 的表达，进而增加了 S1pr1 及其下游靶标 VE-cadherin 的表达，从而抑制血管生成并改善血管稳定性。相反，内皮细胞中 S1pr1 的药理学阻断和遗传缺失均可逆转 miR302-367 对小鼠的抗血管生成和血管稳定作用。肿瘤血管生成具有发育性血管生成的特征，内皮细胞特异性升高 miR302-367 通过相同的 Erk1/2-Klf2-S1pr1 途径限制发芽血管生成并降低血管通透性，从而减少肿瘤生长。
结论
miR302-367 对内皮细胞中 Erk1/2-Klf2-S1pr1 途径的调节促进了我们对血管生成的理解，同时也为肿瘤生长的治疗干预提供了机会。
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