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PMID: 25912305 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Lung tumorigenesis induced by human vascular endothelial growth factor (hVEGF)-A165 overexpression in transgenic mice and amelioration of tumor formation by miR-16.

Oncotarget ·Vol. 6 ·No. 12 ·2015-04-30 ·Pages 10222-38

Tung YT, Huang PW, Chou YC, Lai CW, Wang HP, Ho HC, Yen CC, Tu CY, Tsai TC, Yeh DC, Wang JL, Chong KY, Chen CM

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.

Keywords
VEGF magnetic resonance imaging (MRI) miRNA therapy pulmonary tumorigenesis transgenic mice
MeSH Terms
Animals Carcinogenesis Cell Line, Tumor Chick Embryo Humans Lung Neoplasms/genetics,metabolism,pathology,therapy Magnetic Resonance Imaging/methods Male Mice Mice, Nude Mice, Transgenic MicroRNAs/administration & dosage,genetics Oncogene Proteins, Fusion/biosynthesis,genetics Signal Transduction Transcriptome Vascular Endothelial Growth Factor A/biosynthesis,genetics Xenograft Model Antitumor Assays
Chemicals
MIRN16 microRNA, human MicroRNAs Oncogene Proteins, Fusion VEGFA protein, human Vascular Endothelial Growth Factor A
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Tung Yu-Tang
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
Huang Pin-Wu
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
Chou Yu-Ching
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
Lai Cheng-Wei
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
Wang Hsiu-Po
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
Ho Heng-Chien
Department of Medicine, China Medical University Hospital, Taichung 404, Taiwan.
Yen Chih-Ching
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan. | Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.
Tu Chih-Yen
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan. | Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan.
Tsai Tung-Chou
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan.
Yeh Dah-Cherng
Department of General Surgery and Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan.
Wang Jiun-Long
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan. | Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 407, Taiwan.
Chong Kowit-Yu
Department of Medical Biotechnology and Laboratory Sciences, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan. | Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan 333, Taiwan.
Chen Chuan-Mu
Department of Life Sciences and Agricultural Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan. | Rong-Hsing Translational Medicine Center and iEGG Center, National Chung Hsing University, Taichung 402, Taiwan.
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Article Info
Journal
Oncotarget
Abbr.
Oncotarget
ISSN
1949-2553
DOI
10.18632/oncotarget.3390
Published
2015-04-30
Pages
10222-38
Language
English
Region
United States
NLM ID
101532965
PMCID
PMC4496351
Subset
IM
External Links
PubMed source DOI: 10.18632/oncotarget.3390 PMC Full Text View journal details
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