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

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)85-98
Number of pages14
JournalCirculation Research
Issue number1
Publication statusPublished - Jan 6 2017


  • angiogenesis
  • blood vessel tumor
  • endothelial cells
  • microRNAs

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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