Jingjiang Pi1, Ting Tao1, Tao Zhuang1, Huimin Sun1, Xiaoli Chen1, Jie Liu1, Yu Cheng1, Zuoren Yu1, Helen He Zhu1, Wei-Qiang Gao1, Yuanzhen Suo1, Xunbin Wei1, Paul Chan1, Xiangjian Zheng1, Ying Tian1, Edward Morrisey1, Lin Zhang1, YuZhen Zhang2. 1. 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.). 2. 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.). yzzhang-tj@tongji.edu.cn zhanglin1209@tongji.edu.cn.
Abstract
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.
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.
Authors: Lei Jin; Xue-Mei Ma; Ting-Ting Wang; Yao Yang; Nan Zhang; Na Zeng; Zhi-Gang Bai; Jie Yin; Jun Zhang; Guo-Qian Ding; Zhong-Tao Zhang Journal: Cancer Manag Res Date: 2020-04-23 Impact factor: 3.989
Authors: Yuanping Shi; Yun Liang; Jun Zhang; Miaomei Yu; Min Wang; Lu Zheng; Dongmei Di; Xiaoying Zhang; Guanghua Luo; Ning Xu Journal: Ann Transl Med Date: 2020-03