A microRNA302-367-Erk1/2-Klf2-S1pr1 Pathway Prevents Tumor Growth via Restricting Angiogenesis and Improving Vascular Stability
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 miR302-367cluster 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 down-regulation of Erk1/2 upon 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 anti-angiogenic 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.
- tumor growth
- Sphingosine-1-phosphate receptor 1
- Krüppel-like Factor 2
- Received August 10, 2016.
- Revision received October 2, 2016.
- Accepted October 18, 2016.