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Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis
American Journal of Respiratory and Critical Care Medicine ( IF 24.7 ) Pub Date : 2017-08-30 , DOI: 10.1164/rccm.201610-2157oc
Asawari Korde 1 , Lei Jin 1, 2 , Jian-ge Zhang 3 , Anuradha Ramaswamy 1 , Buqu Hu 1 , Saeed Kolahian 4 , Brenda Juan Guardela 1 , Jose Herazo-Maya 1 , Jill M. Siegfried 5 , Laura Stabile 6 , Margaret A. Pisani 1 , Roy S. Herbst 7 , Naftali Kaminski 1 , Jack A. Elias 8 , Jonathan T. Puchalski 1 , Shervin S. Takyar 1
Affiliation  

Rationale: VEGF down-regulates 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 NSCLC and its specific role in tumor endothelium. Method and measurements: MiR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used VE-cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRAS mutant/P53 knockout (KP) mice, lung-specific VEGF transgenic mice, Lewis lung carcinoma (LLC) xenografts, and primary endothelial cells were used to test the effects of miR-1. Results: In two cohorts of NSCLC patients, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of NSCLC patients. MiR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KRAS mutant P53 knockout (KP) mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 over-expression. Vector-mediated delivery or transgenic over-expression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of LLC xenografts, and decreased tracheal angiogenesis in VEGF transgenic mice. In endothelial cells, miR-1 level was regulated through PI3kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene (Mpl) was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. Conclusion: Endothelial miR-1 is downregulated in NSCLC tumors and controls tumor progression and angiogenesis.

中文翻译:

肺内皮微RNA-1调节肿瘤的生长和血管生成。

原理:VEGF下调肺内皮中的miR-1,并且内皮细胞在肿瘤进展和血管生成中起关键作用。目的:探讨miR-1在非小细胞肺癌中的临床意义及其在肿瘤内皮细胞中的特殊作用。方法和测量:通过Taqman测定法测量MiR-1水平。通过磁性分选分离内皮细胞。我们使用VE-钙粘着蛋白启动子来创建血管特异性miR-1慢病毒载体和诱导型转基因小鼠。使用KRAS突变体/ P53基因敲除(KP)小鼠,肺特异性VEGF转基因小鼠,路易斯肺癌(LLC)异种移植物和原代内皮细胞来测试miR-1的作用。结果:在两个非小细胞肺癌患者队列中,肿瘤中的miR-1水平低于无癌组织。肿瘤miR-1水平与NSCLC患者的整体生存率相关。从NSCLC肿瘤和KRAS突变P53基因敲除(KP)小鼠模型的荷瘤肺中分离的内皮细胞中,MiR-1水平也较低。我们通过测试血管特异性miR-1过表达的作用,检查了降低miR-1水平的重要性。载体介导的内皮细胞中miR-1的传递或转基因过表达减少了KP小鼠的肿瘤负担,降低了LLC异种移植物的生长和血管,并降低了VEGF转基因小鼠的气管血管生成。在内皮细胞中,miR-1的水平是通过PI3激酶调节的,并且可以特异性地控制增殖,我们通过测试血管特异性miR-1过表达的作用,检查了降低miR-1水平的重要性。载体介导的内皮细胞中miR-1的传递或转基因过表达减少了KP小鼠的肿瘤负担,降低了LLC异种移植物的生长和血管,并降低了VEGF转基因小鼠的气管血管生成。在内皮细胞中,miR-1的水平是通过PI3激酶调节的,并且可以特异性地控制增殖,我们通过测试血管特异性miR-1过表达的作用,检查了降低miR-1水平的重要性。载体介导的内皮细胞中miR-1的传递或转基因过表达减少了KP小鼠的肿瘤负担,降低了LLC异种移植物的生长和血管,并降低了VEGF转基因小鼠的气管血管生成。在内皮细胞中,miR-1的水平是通过PI3激酶调节的,并且可以特异性地控制增殖,从头开始DNA合成和ERK1 / 2激活。miR-1靶向骨髓增生性白血病致癌基因(Mpl)在肺内皮中,并调节肿瘤的生长和血管生成。结论:内皮细胞miR-1在NSCLC肿瘤中被下调,并控制肿瘤的进展和血管生成。
更新日期:2017-09-05
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