Modulation of cystatin A expression in human airway epithelium related to genotype, smoking, COPD, and lung cancer.
Modulation of cystatin A expression in human airway epithelium related to genotype, smoking, COPD, and lung cancer.
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DOI：
10.1158/0008-5472.can-10-2046
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发表时间：
2011-04-01
期刊：
影响因子：
11.2
通讯作者：
Crystal RG
中科院分区：
文献类型：
--
作者：
Butler MW;Fukui T;Salit J;Shaykhiev R;Mezey JG;Hackett NR;Crystal RG
胱抑素A（基因：CSTA）在非小细胞肺癌（NSCLC）和发育不良的人支气管上皮中表达上调。慢性阻塞性肺疾病（COPD）是一种小气道上皮（SAE）疾病，与非小细胞肺癌（尤其是鳞状细胞癌，SCC）独立相关，但仅发生在吸烟者中，我们假设遗传变异、吸烟和COPD调节SAE中CSTA基因表达水平，并在SCC中进一步上调。通过芯片技术评估178例SAE患者（健康非吸烟者（n=60）、健康吸烟者（n=82）和慢性阻塞性肺病吸烟者（n=36））的基因表达，并在一个亚群（n=52）中获得相应的大气道上皮（LAE）数据。采用SNP芯片对血液DNA进行基因分型。CSTA基因上游的12个snp均与CSTA SAE基因表达显著相关（p<0.04 ~ 5 × 10−4）。COPD吸烟者SAE中CSTA基因表达水平（28.4±2.0）高于健康吸烟者（19.9±1.4,p<10−3），而健康吸烟者的CSTA基因表达水平又高于非吸烟者（16.1±1.1,p<0.04）。CSTA LAE基因表达也与吸烟相关（p<10−3）。使用可比较的公开可获得的NSCLC表达数据，CSTA在SCC与LAE中上调（p<10−2），在腺癌与SAE中下调（p<10−7）。所有表型与CSTA对组织蛋白酶的比例基因表达显著不同相关。这些数据表明，CSTA在人气道上皮中的表达调控受到遗传变异、吸烟和COPD的影响，并在SCC中进一步上调，在考虑CSTA在NSCLC发病中的作用时应考虑到这些因素。
Cystatin A (gene: CSTA), is up-regulated in non-small-cell lung cancer(NSCLC) and dysplastic vs normal human bronchial epithelium. In the context that chronic obstructive pulmonary disease (COPD), a small airway epithelium (SAE) disorder, is independently associated with NSCLC(especially squamous cell carcinoma, SCC), but only occurs in a subset of smokers, we hypothesized that genetic variation, smoking and COPD modulate CSTA gene expression levels in SAE, with further up-regulation in SCC. Gene expression was assessed by microarray in SAE of 178 individuals [healthy nonsmokers (n=60), healthy smokers (n=82), and COPD smokers (n=36)], with corresponding large airway epithelium (LAE) data in a subset (n=52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were all significantly associated with CSTA SAE gene expression(p<0.04 to 5 × 10 −4). CSTA gene expression levels in SAE were higher in COPD smokers (28.4 ± 2.0) than healthy smokers (19.9 ± 1.4, p<10−3), who in turn had higher levels than nonsmokers(16.1 ± 1.1, p<0.04). CSTA LAE gene expression was also smoking-responsive (p<10−3). Using comparable publicly available NSCLC expression data, CSTA was up-regulated in SCC vs LAE (p<10−2) and down-regulated in adenocarcinoma vs SAE (p <10−7). All phenotypes were associated with significantly different proportional gene expression of CSTA to cathepsins. The data demonstrate that regulation of CSTA expression in human airway epithelium is influenced by genetic variability, smoking, and COPD, and is further up-regulated in SCC, all of which should be taken into account when considering the role of CSTA in NSCLC pathogenesis.