Abstract
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.
Highlights
Lung cancer is the leading cause of cancer related death around the world [1]
The follow-up IPA (Ingenuity Pathway Analysis) study of the differentially expressed genes suggested that a number of oncogenic pathways/networks, i.e., PI3K/AKT, Myc, NF-ĸB, Chemokine, Telomerase, EGF, ERK/MAPK, and JAK/Stat signaling pathways were activated in the bronchial airways of mice harboring preneoplastic squamous cell carcinoma (SCC) lesions
Gene-expression signatures have been developed from bronchial brush samples to infer early genomic events important to lung cancer etiology in human populations, no corresponding research has been done in mouse models
Summary
Lung cancer is the leading cause of cancer related death around the world [1]. Lung squamous cell carcinoma (SCC) is a major category of non-small cell lung cancers (NSCLC), accounting for about 25–30% of total lung cancer cases in the US population. As a consequence of prolonged exposure to environmental toxicants such as cigarette smoke or air pollution, 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 bronchial epithelium that contain molecular lesions such as mutations in an oncogene or tumor suppressor gene [10,11,12,13,14]. Tissue samples from this extended injured area can be collected in a less invasive manner by bronchial brushing and have been used to develop a gene expression–based biomarker signature for distinguishing lung cancer in smokers [15]. We wished to compare RNA expression results in the NTCU mouse model and compare it with human data
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