Molecular Characterization of the Peripheral Airway Field of Cancerization in Lung Adenocarcinoma

Field of cancerization in the airway epithelium has been increasingly examined to understand early pathogenesis of non-small cell lung cancer. However, the extent of field of cancerization throughout the lung airways is unclear. Here we sought to determine the differential gene and microRNA expressions associated with field of cancerization in the peripheral airway epithelial cells of patients with lung adenocarcinoma. We obtained peripheral airway brushings from smoker controls (n=13) and from the lung contralateral to the tumor in cancer patients (n=17). We performed gene and microRNA expression profiling on these peripheral airway epithelial cells using Affymetrix GeneChip and TaqMan Array. Integrated gene and microRNA analysis was performed to identify significant molecular pathways. We identified 26 mRNAs and 5 miRNAs that were significantly (FDR <0.1) up-regulated and 38 mRNAs and 12 miRNAs that were significantly down-regulated in the cancer patients when compared to smoker controls. Functional analysis identified differential transcriptomic expressions related to tumorigenesis. Integration of miRNA-mRNA data into interaction network analysis showed modulation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway in the contralateral lung field of cancerization. In conclusion, patients with lung adenocarcinoma have tumor related molecules and pathways in histologically normal appearing peripheral airway epithelial cells, a substantial distance from the tumor itself. This finding can potentially provide new biomarkers for early detection of lung cancer and novel therapeutic targets.

气道上皮癌化区域（field of cancerization）的相关研究日益增多，以期阐明非小细胞肺癌的早期发病机制。然而，癌化区域在全肺气道中的分布范围仍不明确。本研究旨在明确肺腺癌患者外周气道上皮细胞中，与癌化区域相关的差异基因与微小RNA（microRNA）表达谱差异。我们分别从吸烟健康对照人群（n=13）以及肺癌患者的肿瘤对侧肺组织中获取外周气道刷检样本（癌症患者组n=17）。采用Affymetrix基因芯片与TaqMan阵列，对上述外周气道上皮细胞开展基因与微小RNA表达谱分析。通过整合基因与微小RNA数据分析，以筛选具有统计学意义的分子通路。相较于吸烟健康对照人群，癌症患者组中共鉴定出26种显著上调（错误发现率FDR <0.1）的信使RNA（mRNA）以及5种微小RNA（miRNA），同时鉴定出38种显著下调的信使RNA与12种微小RNA。功能分析显示，差异转录组表达与肿瘤发生密切相关。将miRNA-mRNA数据整合至相互作用网络分析后，发现细胞外调节蛋白激酶/丝裂原活化蛋白激酶（extracellular signal-regulated kinase/mitogen-activated protein kinase, ERK/MAPK）通路在肿瘤对侧肺的癌化区域中受到调控。综上，肺腺癌患者在远离原发肿瘤、组织学外观正常的外周气道上皮细胞中，已存在与肿瘤相关的分子及通路异常。这一发现可为肺癌早期检测提供新型生物标志物，并为开发全新治疗靶点提供理论依据。