Abstract
Many studies have shown that vascular endothelial growth factor (VEGF), especially the human VEGF-A165 (hVEGF-A165) isoform, is a key proangiogenic factor that is overexpressed in lung cancer. We generated transgenic mice that overexpresses hVEGF-A165 in lung-specific Clara cells to investigate the development of pulmonary adenocarcinoma. In this study, three transgenic mouse strains were produced by pronuclear microinjection, and Southern blot analysis indicated similar patterns of the foreign gene within the genomes of the transgenic founder mice and their offspring. Accordingly, hVegf-A165 mRNA was expressed specifically in the lung tissue of the transgenic mice. Histopathological examination of the lung tissues of the transgenic mice showed that hVEGF-A165 overexpression induced bronchial inflammation, fibrosis, cysts, and adenoma. Pathological section and magnetic resonance imaging (MRI) analyses demonstrated a positive correlation between the development of pulmonary cancer and hVEGF expression levels, which were determined by immunohistochemistry, qRT-PCR, and western blot analyses. Gene expression profiling by cDNA microarray revealed a set of up-regulated genes (hvegf-A165, cyclin b1, cdc2, egfr, mmp9, nrp-1, and kdr) in VEGF tumors compared with wild-type lung tissues. In addition, overexpressing hVEGF-A165 in Clara cells increases CD105, fibrogenic genes (collagen α1, α-SMA, TGF-β1, and TIMP1), and inflammatory cytokines (IL-1, IL-6, and TNF-α) in the lungs of hVEGF-A165-overexpressing transgenic mice as compared to wild-type mice. We further demonstrated that the intranasal administration of microRNA-16 (miR-16) inhibited lung tumor growth by suppressing VEGF expression via the intrinsic and extrinsic apoptotic pathways. In conclusion, hVEGF-A165 transgenic mice exhibited complex alterations in gene expression and tumorigenesis and may be a relevant model for studying VEGF-targeted therapies in lung adenocarcinoma.
Highlights
Despite major advances in cancer therapeutics, the survival rate for patients with lung cancer has not significantly improved, even in the era of targeted therapy [1]
The transgenic line Tg3 exhibited a higher level of www.impactjournals.com/oncotarget hvegf-A165 expression than the transgenic line Tg2, while no hvegf-A165 expression was detected in the transgenic line Tg1 or the wild-type mice
After three intranasal administrations of 20 μg miR-16 or mock miR per mouse once a week, we found that miR-16, which lowered the expression of vascular endothelial growth factor (VEGF) in both lung tissues (Figure 8B and 8C) and circulation blood (Figure 8D) (p < 0.01), affected the formation of lung tumors in > 12-month-old www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget lung-specific hVEGF-A165 overexpressing transgenic mice (Figure 8A)
Summary
Despite major advances in cancer therapeutics, the survival rate for patients with lung cancer has not significantly improved, even in the era of targeted therapy [1]. Mouse models for human lung cancer have been developed in recent years to understand the mechanisms of the disease, to identify several potential molecular targets and to develop novel “targeted therapies”. The primary cause of pulmonary cancer consists of gene mutations induced by carcinogens contained in items, such as the cigarette smoke inhaled by long-term addicts or environmentally polluted air. In addition to cigarette addiction, the long-term inflammatory response in the lungs caused by allergens in the air may cause pulmonary adenocarcinoma. Chronic diseases in the lungs and family inheritance are two common causes of pulmonary adenocarcinoma. There is evidence that gene mutations (k-ras, cyclin d1, bcl, rb, and apc) play a role in the formation of human lung adenocarcinoma [6, 7]
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