Boelens Mirjam C, van den Berg Anke, Fehrmann Rudolf S N, Geerlings Marie, de Jong Wouter K, te Meerman Gerard J, Sietsma Hannie, Timens Wim, Postma Dirkje S, Groen Harry J M
Department of Pathology, University Medical Centre Groningen, Groningen, The Netherlands.
J Pathol. 2009 Jun;218(2):182-91. doi: 10.1002/path.2520.
Cigarette smoking is the main risk factor for the development of squamous cell lung carcinoma (SCC). However, the smoking-related molecular changes in SCC have not been studied. Gene expression studies in both histologically normal bronchial epithelium and SCC epithelial samples identified genes differentially expressed between current and ex-smokers. Subsequently, expression levels of the smoking-related genes in normal bronchial epithelium were compared with those in SCC cells, since we hypothesized that the smoking-induced changes would be also deregulated in SCC. Gene expression profiles were generated using Agilent whole human genome microarrays on laser-microdissected normal bronchial epithelium and SCC samples. Expression levels of 246 genes, mainly related to oxidative stress response, were significantly different between normal bronchial epithelium of current and ex-smokers. Such a differential gene expression profile did not exist in SCC cells of smokers and ex-smokers. Interestingly, when comparing SCC and normal bronchial epithelium from ex-smokers, the vast majority of these 246 genes were also deregulated in SCC. When comparing SCC with normal epithelium from smokers, 22% of the up-regulated genes showed a similar high expression in SCC whereas 79% of the down-regulated genes were even further reduced in SCC as compared to current smokers. The down-regulated genes included several tumour suppressor genes, such as C9orf9, INHBB, LRIG1, SCGB3A1, SERPINI2, STEAP3 and ZMYND10. Thus, our study shows that the majority of genes up-regulated in normal bronchial epithelium of current smokers show similar high expression levels in SCC, while down-regulated genes are even further repressed in SCC. Our data indicate that smoking-related changes in normal bronchial epithelial cells persist in malignant transformed squamous cells.
吸烟是鳞状细胞肺癌（SCC）发生的主要危险因素。然而，SCC中与吸烟相关的分子变化尚未得到研究。对组织学正常的支气管上皮和SCC上皮样本进行的基因表达研究确定了当前吸烟者和既往吸烟者之间差异表达的基因。随后，将正常支气管上皮中吸烟相关基因的表达水平与SCC细胞中的表达水平进行比较，因为我们假设吸烟诱导的变化在SCC中也会失调。使用安捷伦全人类基因组微阵列对激光显微切割的正常支气管上皮和SCC样本生成基因表达谱。246个主要与氧化应激反应相关的基因的表达水平在当前吸烟者和既往吸烟者的正常支气管上皮之间存在显著差异。吸烟者和既往吸烟者的SCC细胞中不存在这种差异基因表达谱。有趣的是，当比较既往吸烟者的SCC和正常支气管上皮时，这246个基因中的绝大多数在SCC中也失调。当将SCC与吸烟者的正常上皮进行比较时，22%的上调基因在SCC中显示出相似的高表达，而79%的下调基因在SCC中与当前吸烟者相比甚至进一步降低。下调的基因包括几个肿瘤抑制基因，如C9orf9、INHBB、LRIG1、SCGB3A1、SERPINI2、STEAP3和ZMYND10。因此，我们的研究表明，当前吸烟者正常支气管上皮中上调的大多数基因在SCC中显示出相似的高表达水平，而下调基因在SCC中甚至进一步受到抑制。我们的数据表明，正常支气管上皮细胞中与吸烟相关的变化在恶性转化的鳞状细胞中持续存在。
