Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents
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Donghai Xiong1,2,*, Jing Pan1,2,*, Qi Zhang1,2,*, Eva Szabo3, Mark Steven Miller3, Ronald A. Lubet3, Ming You1,2, Yian Wang1,2
1Cancer Center, Medical College of Wisconsin, WI 53226, USA
2Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
3Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD 20850, USA
*These authors contributed equally to this work
Ming You, email: [email protected]
Yian Wang, email: [email protected]
Keywords: AUC (area under the curve), GSEA (gene set enrichment analysis), IPA (Ingenuity Pathway Analysis), PPAR (peroxisome proliferator-activated receptor gamma), SCC (squamous cell carcinoma)
Received: September 22, 2016 Accepted: November 07, 2016 Published: December 07, 2016
Due to exposure to environmental toxicants, a “field cancerization” effect occurs in the lung resulting in the development of a field of initiated but morphologically normal appearing cells in the damaged epithelium of bronchial airways with dysregulated gene expression patterns. Using a mouse model of lung squamous cell carcinoma (SCC), we performed transcriptome sequencing (RNA-Seq) to profile bronchial airway gene expression and found activation of the PI3K and Myc signaling networks in cytologically normal bronchial airway epithelial cells of mice with preneopastic lung SCC lesions, which was reversed by treatment with the PI3K Inhibitor XL-147 and pioglitazone, respectively. Activated MYC signaling was also present in premalignant and tumor tissues from human lung SCC patients. In addition, we identified a key microRNA, mmu-miR-449c-5p, whose suppression significantly up-regulated Myc expression in the normal bronchial airway epithelial cells of mice with early stage SCC lesions. We developed a novel bronchial genomic classifier in mice and validated it in humans. In the classifier, Ppbp (pro-platelet basic protein) was overexpressed 115 fold in the bronchial airways of mice with preneoplastic lung SCC lesions. This is the first report that demonstrates Ppbp as a novel biomarker in the bronchial airway for lung cancer diagnosis.
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