Data from Modulation of Cystatin A Expression in Human Airway Epithelium Related to Genotype, Smoking, COPD, and Lung Cancer

Abstract

<div>Abstract<p>The cathepsin inhibitor Cystatin A (<i>CSTA</i>) has antiapoptotic properties linked with neoplastic changes in squamous cell epithelium, where it has been proposed as a diagnostic and prognostic marker of lung cancer. Notably, cystatin A is upregulated in dysplastic epithelium, prompting us to hypothesize that it might be modulated in chronic obstructive pulmonary disease (COPD), a small airway epithelial (SAE) disorder that is a risk factor for non–small cell lung cancer (NSCLC) in a subset of smokers. Here we report that genetic variation, smoking, and COPD can all elevate levels of <i>CSTA</i> expression in lung small airway epithelia, with still further upregulation in squamous cell carcinoma (SCC), an NSCLC subtype. We examined SAE gene expression in 178 individuals, including healthy nonsmokers (<i>n</i> = 60), healthy smokers (<i>n</i> = 82), and COPD smokers (<i>n</i> = 36), with corresponding large airway epithelium (LAE) data included in a subset of subjects (<i>n</i> = 52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the <i>CSTA</i> gene were found to associate with its expression in SAE. Levels were higher in COPD smokers than in healthy smokers, who, in turn, had higher levels than nonsmokers. <i>CSTA</i> gene expression in LAE was also smoking-responsive. Using publicly available NSCLC expression data we also found that <i>CSTA</i> was upregulated in SCC versus LAE and downregulated in adenocarcinoma versus smoke-exposed SAE. All phenotypes were associated with different proportional expression of <i>CSTA</i> to cathepsins. Our findings establish that genetic variability, smoking, and COPD all influence <i>CSTA</i> expression, as does SCC, supporting the concept that <i>CSTA</i> may make pivotal contributions to NSCLC pathogenesis in both early and late stages of disease development. <i>Cancer Res; 71(7); 2572–81. ©2011 AACR</i>.</p></div>