A MicroRNA302-367-Erk1/2-Klf2-S1pr1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Improving Vascular Stability

Jingjiang Pi; Ting Tao; Tao Zhuang; Huimin Sun; Xiaoli Chen; Jie Liu; Yu Cheng; Zuoren Yu; Helen He Zhu; Wei-Qiang Gao; Yuanzhen Suo; Xunbin Wei; Paul Chan; Xiangjian Zheng; Ying Tian; Edward Morrisey; Lin Zhang; YuZhen Zhang

doi:10.1161/CIRCRESAHA.116.309757

A MicroRNA302-367-Erk1/2-Klf2-S1pr1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Improving Vascular Stability

Circ Res. 2017 Jan 6;120(1):85-98. doi: 10.1161/CIRCRESAHA.116.309757. Epub 2016 Oct 18.

Authors

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

Affiliations

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.

PMID: 27756792
DOI: 10.1161/CIRCRESAHA.116.309757

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.

Keywords: angiogenesis; blood vessel tumor; endothelial cells; microRNAs.

MeSH terms

Angiogenesis Inhibitors / biosynthesis
Animals
Carcinoma, Lewis Lung
Coculture Techniques
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Kruppel-Like Transcription Factors / biosynthesis*
MAP Kinase Signaling System / physiology*
Melanoma, Experimental
Mice
Mice, Transgenic
MicroRNAs / biosynthesis*
Neoplasms / metabolism*
Neoplasms / pathology
Neoplasms / prevention & control
Neovascularization, Pathologic / metabolism*
Neovascularization, Pathologic / pathology
Neovascularization, Pathologic / prevention & control
Receptors, Lysosphingolipid / biosynthesis*
Sphingosine-1-Phosphate Receptors
Xenograft Model Antitumor Assays / methods

Substances

Angiogenesis Inhibitors
Klf2 protein, mouse
Kruppel-Like Transcription Factors
MIRN302 microRNA, mouse
MIRN367 microRNA, mouse
MicroRNAs
Receptors, Lysosphingolipid
S1pr1 protein, mouse
Sphingosine-1-Phosphate Receptors

Grants and funding

R00 HL111348/HL/NHLBI NIH HHS/United States