Pandiri Arun R, Sills Robert C, Ziglioli Vincent, Ton Thai-Vu T, Hong Hue-Hua L, Lahousse Stephanie A, Gerrish Kevin E, Auerbach Scott S, Shockley Keith R, Bushel Pierre R, Peddada Shyamal D, Hoenerhoff Mark J
Cellular and Molecular Pathology Branch, National Toxicology Program-NTP, National Institute of Environmental Health Sciences-NIEHS, Research Triangle Park, North Carolina, USA.
Toxicol Pathol. 2012 Dec;40(8):1141-59. doi: 10.1177/0192623312447543. Epub 2012 Jun 11.
Lung cancer is the leading cause of cancer-related death in people and is mainly due to environmental factors such as smoking and radon. The National Toxicology Program (NTP) tests various chemicals and mixtures for their carcinogenic hazard potential. In the NTP chronic bioassay using B6C3F1 mice, the incidence of lung tumors in treated and control animals is second only to the liver tumors. In order to study the molecular mechanisms of chemically induced lung tumors, an understanding of the genetic changes that occur in spontaneous lung (SL) tumors from untreated control animals is needed. The authors have evaluated the differential transcriptomic changes within SL tumors compared to normal lungs from untreated age-matched animals. Within SL tumors, several canonical pathways associated with cancer (eukaryotic initiation factor 2 signaling, RhoA signaling, PTEN signaling, and mammalian target of rapamycin signaling), metabolism (Inositol phosphate metabolism, mitochondrial dysfunction, and purine and pyramidine metabolism), and immune responses (FcγR-mediated phagocytosis, clathrin-mediated endocytosis, interleukin 8 signaling, and CXCR4 signaling) were altered. Meta-analysis of murine SL tumors and human non-small cell lung cancer transcriptomic data sets revealed a high concordance. These data provide important information on the differential transcriptomic changes in murine SL tumors that will be critical to our understanding of chemically induced lung tumors and will aid in hazard analysis in the NTP 2-year carcinogenicity bioassays.
肺癌是导致人类癌症相关死亡的主要原因，主要归因于吸烟和氡等环境因素。美国国家毒理学计划（NTP）对各种化学品和混合物的致癌潜在危害进行测试。在使用B6C3F1小鼠的NTP慢性生物测定中，经处理动物和对照动物的肺肿瘤发生率仅次于肝肿瘤。为了研究化学诱导肺肿瘤的分子机制，需要了解未处理对照动物自发肺（SL）肿瘤中发生的基因变化。作者评估了与未处理的年龄匹配动物的正常肺相比，SL肿瘤内的差异转录组变化。在SL肿瘤内，与癌症相关的几种典型途径（真核起始因子2信号传导、RhoA信号传导、PTEN信号传导和雷帕霉素哺乳动物靶标信号传导）、代谢（肌醇磷酸代谢、线粒体功能障碍以及嘌呤和嘧啶代谢）和免疫反应（FcγR介导的吞噬作用、网格蛋白介导的内吞作用、白细胞介素8信号传导和CXCR4信号传导）发生了改变。对小鼠SL肿瘤和人类非小细胞肺癌转录组数据集的荟萃分析显示出高度一致性。这些数据提供了有关小鼠SL肿瘤中差异转录组变化的重要信息，这对于我们理解化学诱导的肺肿瘤至关重要，并将有助于NTP两年致癌性生物测定中的危害分析。
