Asawari Korde1, Lei Jin1,2, Jian-Ge Zhang3, Anuradha Ramaswamy1, Buqu Hu1, Saeed Kolahian4, Brenda Juan Guardela1, Jose Herazo-Maya1, Jill M Siegfried5, Laura Stabile6, Margaret A Pisani1, Roy S Herbst7, Naftali Kaminski1, Jack A Elias8, Jonathan T Puchalski1, Shervin S Takyar1. 1. 1 Section of Pulmonary, Critical Care, and Sleep Medicine and. 2. 2 Cleveland Clinic Cole Eye Institute and Lerner Research Institute, Cleveland, Ohio. 3. 3 Department of Medicinal Chemistry, School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, China. 4. 4 Department of Pharmacology and Experimental Therapy, University of Tübingen, Tübingen, Germany. 5. 5 Department of Pharmacology, Masonic Cancer Center, University of Minnesota Medical School, Minneapolis, Minnesota. 6. 6 Department of Pharmacology and Chemical Biology, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, Pennsylvania; and. 7. 7 Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, Connecticut. 8. 8 Division of Biology and Medicine, Warren Alpert School of Medicine at Brown University, Providence, Rhode Island.
Abstract
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.
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 transgenicmouse. 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.
Authors: James F Reid; Viktorija Sokolova; Eugenio Zoni; Andrea Lampis; Sara Pizzamiglio; Claudia Bertan; Susanna Zanutto; Federica Perrone; Tiziana Camerini; Gianfrancesco Gallino; Paolo Verderio; Ermanno Leo; Silvana Pilotti; Manuela Gariboldi; Marco A Pierotti Journal: Mol Cancer Res Date: 2012-02-16 Impact factor: 5.852
Authors: Yihai Cao; Jack Arbiser; Robert J D'Amato; Patricia A D'Amore; Donald E Ingber; Robert Kerbel; Michael Klagsbrun; Sharon Lim; Marsha A Moses; Bruce Zetter; Harold Dvorak; Robert Langer Journal: Sci Transl Med Date: 2011-12-21 Impact factor: 17.956
Authors: Maor Sauler; Maxime Lamontagne; Eric Finnemore; Jose D Herazo-Maya; John Tedrow; Xuchen Zhang; Julia E Morneau; Frank Sciurba; Wim Timens; Peter D Paré; Patty J Lee; Naftali Kaminski; Yohan Bossé; Jose L Gomez Journal: Eur Respir J Date: 2018-10-04 Impact factor: 16.671