Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents.
Bronchial airway gene expression signatures in mouse lung squamous cell carcinoma and their modulation by cancer chemopreventive agents.
复制标题
DOI：
10.18632/oncotarget.13806
复制
发表时间：
2017-03-21
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Xiong D;Pan J;Zhang Q;Szabo E;Miller MS;Lubet RA;You M;Wang Y
由于暴露于环境毒物，在肺中发生“现场癌变”效应，导致在支气管气道的受损上皮中形成具有失调的基因表达模式的初始但形态正常的细胞场。使用肺鳞状细胞癌（SCC）小鼠模型，我们进行了转录组测序（RNA-Seq），以分析支气管气道基因表达，并发现在细胞学正常的支气管气道上皮细胞中PI 3 K和Myc信号传导网络的活化，这些细胞具有癌前肺SCC病变，分别用PI 3 K抑制剂XL-147和吡格列酮治疗可逆转。活化的MYC信号也存在于人肺SCC患者的癌前病变和肿瘤组织中。此外，我们鉴定了一种关键的microRNA，mmu-miR-449 c-5 p，其抑制显著上调了早期SCC病变小鼠正常支气管气道上皮细胞中Myc的表达。我们在小鼠中开发了一种新的支气管基因组分类器，并在人类中进行了验证。在分类器中，Ppbp（前血小板碱性蛋白）在具有癌前肺SCC病变的小鼠的支气管气道中过表达115倍。这是第一个报告，证明Ppbp作为一种新的生物标志物在支气管气道肺癌诊断。
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.