Qian Xuemin, Khammanivong Ali, Song Jung Min, Teferi Fitsum, Upadhyaya Pramod, Dickerson Erin, Kassie Fekadu
Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street SE, Minneapolis, MN, 55455, USA.
Inflamm Res. 2015 May;64(5):343-61. doi: 10.1007/s00011-015-0815-z. Epub 2015 Mar 21.
Chronic pulmonary inflammation has been consistently shown to increase the risk of lung cancer. Therefore, assessing the molecular links between the two diseases and identification of chemopreventive agents that inhibit inflammation-driven lung tumorigenesis is indispensable.
Female A/J mice were treated with the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and lipopolysaccharide (LPS), a potent inflammatory agent and constituent of tobacco smoke, and maintained on control diet or diet supplemented with the chemopreventive agents indole-3-carbinol (I3C) and/or silibinin (Sil). At the end of the study, mice were sacrificed and tumors on the surface of the lung were counted and gene expression levels in lung tissues were determined by RNA sequencing.
The mean number of lung tumors induced by NNK and NNK + LPS was 5 and 15 tumors/mouse, respectively. Dietary supplementation with the combination of I3C and Sil significantly reduced the size and multiplicity (by 50 %) of NNK + LPS-induced lung tumors. Also, we found that 330, 2957, and 1143 genes were differentially regulated in mice treated with NNK, LPS, and NNK + LPS, respectively. The inflammatory response of lung tumors to LPS, as determined by the number of proinflammatory genes with altered gene expression or the level of alteration, was markedly less than that of normal lungs. Among 1143 genes differentially regulated in the NNK + LPS group, the expression of 162 genes and associated signaling pathways was significantly modulated by I3C and/or Sil + I3C. These genes include cytokines, chemokines, putative oncogenes and tumor suppressor genes and Ros1, AREG, EREG, Cyp1a1, Arntl, and Npas2.
To our knowledge, this is the first report that provides insight into genes that are differentially expressed during inflammation-driven lung tumorigenesis and the modulation of these genes by chemopreventive agents.
慢性肺部炎症一直被证明会增加患肺癌的风险。因此，评估这两种疾病之间的分子联系以及鉴定抑制炎症驱动的肺癌发生的化学预防剂是必不可少的。
雌性A/J小鼠用烟草烟雾致癌物4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮（NNK）和脂多糖（LPS，一种强效炎症剂和烟草烟雾的成分）进行处理，并维持在对照饮食或补充有化学预防剂吲哚-3-甲醇（I3C）和/或水飞蓟宾（Sil）的饮食上。在研究结束时，处死小鼠并计数肺表面的肿瘤，通过RNA测序确定肺组织中的基因表达水平。
NNK和NNK + LPS诱导的肺肿瘤平均数量分别为每只小鼠5个和15个肿瘤。饮食中添加I3C和Sil的组合显著降低了NNK + LPS诱导的肺肿瘤的大小和数量（降低了50%）。此外，我们发现分别用NNK、LPS和NNK + LPS处理的小鼠中有330、2957和1143个基因受到差异调节。通过基因表达改变的促炎基因数量或改变水平确定，肺肿瘤对LPS的炎症反应明显小于正常肺。在NNK + LPS组中差异调节的1143个基因中，162个基因的表达以及相关信号通路受到I3C和/或Sil + I3C的显著调节。这些基因包括细胞因子、趋化因子、假定的癌基因和肿瘤抑制基因以及Ros1、AREG（双调蛋白）、EREG（上皮调节蛋白）、Cyp1a1（细胞色素P450 1A1）、Arntl（芳香烃受体核转运蛋白样蛋白1）和Npas2（神经元 PAS 结构域蛋白 2）。
据我们所知，这是第一份深入了解炎症驱动的肺癌发生过程中差异表达的基因以及化学预防剂对这些基因调节作用的报告。
