Rationale: Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. Objectives: To examine the clinical significance of miR-1 in non–small cell lung cancer (NSCLC) and its specific role in tumor endothelium. Methods: miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRASG12D mut/Trp53-/- (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1. Measurements and Main Results: In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3-kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. Conclusions: Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis.
|Original language||English (US)|
|Number of pages||13|
|Journal||American journal of respiratory and critical care medicine|
|State||Published - Dec 1 2017|
Bibliographical noteFunding Information:
*These authors contributed equally to this work. Supported by the NHLBI (K99/R00) and the American Lung Association Lung Cancer Discovery Award. Author Contributions: L.J., A.K., J.-g.Z., and S.K., experimental work. A.K. took part in writing and formatting the manuscript. A.R., clinical data collection and analysis. B.H., data analysis. B.J.G. and J.H.-M., collection and processing of clinical samples and data analysis. J.M.S. and L.S., collection of clinical samples. M.A.P., design of the clinical study. R.S.H., study conception and design. N.K., review of the manuscript. J.A.E., conception and design of VEGF transgenic studies. J.T.P. and A.R., collection and processing of clinical samples. S.S.T., study conception and design, experimental work, and writing and editing of the manuscript.
Supported by the NHLBI (K99/R00) and the American Lung Association Lung Cancer Discovery Award. Acknowledgment: The authors thank Daniel J. Boffa (Yale Section of Thoracic Surgery) for his support and for providing tissues for our studies, and Maria Haslip (Yale Pulmonary and Critical Care Section) for her help with cellular apoptosis studies.
Copyright © 2017 by the American Thoracic Society.
- Lung cancer
- Tumor microenvironment
- Vascular endothelial growth factor blockers