comparative functional genomics analysis of nnk tobacco-carcinogen induced lung adenocarcinoma development in gprc5a-knockout mice比较功能基因组学分析gprc5a-knockout nnk tobacco-carcinogen诱导肺腺癌发展的老鼠.pdf

Comparative Functional Genomics Analysis of NNK Tobacco-Carcinogen Induced Lung Adenocarcinoma Development in Gprc5a-Knockout Mice 1. 1. 1 2 1 1 Junya Fujimoto , Humam Kadara , Taoyan Men , Carolyn van Pelt , Dafna Lotan , Reuben Lotan * 1 Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America, 2 Department of Veterinary Medicine and Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America Abstract Background: Improved understanding of lung cancer development and progression, including insights from studies of animal models, are needed to combat this fatal disease. Previously, we found that mice with a knockout (KO) of G-protein coupled receptor 5A (Gprc5a) develop lung tumors after a long latent period (12 to 24 months). Methodology/Principal Findings: To determine whether a tobacco carcinogen will enhance tumorigenesis in this model, we administered 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) i.p. to 2-months old Gprc5a-KO mice and sacrificed groups (n = 5) of mice at 6, 9, 12, and 18 months later. Compared to control Gprc5a-KO mice, NNK-treated mice developed lung tumors at least 6 months earlier, exhibited 2- to 4-fold increased tumor incidence and multiplicity, and showed a dramatic increase in lesion size. A gene expression signature, NNK-ADC, of differentially expressed genes derived by transcriptome analysis of epithelial cell lines from normal lungs of Gprc5a-KO mice and from NNK-induced adenocarcinoma was highly similar to differential expression patterns observed between normal and tumorigenic human lung cells. The