title: Smoking-induced CXCL14 expression in the human airway epithelium links chronic obstructive pulmonary disease to lung cancer.
abstract: CXCL14, a recently described epithelial cytokine, plays putative multiple roles in inflammation and carcinogenesis. In the context that chronic obstructive pulmonary disease (COPD) and lung cancer are both smoking-related disorders associated with airway epithelial disorder and inflammation, we hypothesized that the airway epithelium responds to cigarette smoking with altered CXCL14 gene expression, contributing to the disease-relevant phenotype. Using genome-wide microarrays with subsequent immunohistochemical analysis, the data demonstrate that the expression of CXCL14 is up-regulated in the airway epithelium of healthy smokers and further increased in COPD smokers, especially within hyperplastic/metaplastic lesions, in association with multiple genes relevant to epithelial structural integrity and cancer. In vitro experiments revealed that the expression of CXCL14 is induced in the differentiated airway epithelium by cigarette smoke extract, and that epidermal growth factor mediates CXCL14 up-regulation in the airway epithelium through its effects on the basal stem/progenitor cell population. Analyses of two independent lung cancer cohorts revealed a dramatic up-regulation of CXCL14 expression in adenocarcinoma and squamous-cell carcinoma. High expression of the COPD-associated CXCL14-correlating cluster of genes was linked in lung adenocarcinoma with poor survival. These data suggest that the smoking-induced expression of CXCL14 in the airway epithelium represents a novel potential molecular link between smoking-associated airway epithelial injury, COPD, and lung cancer.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Ave., New York, NY 10065, USA.
authors.forename: Renat
authors.initials: R
authors.lastname: Shaykhiev
authors.forename: Rachel
authors.initials: R
authors.lastname: Sackrowitz
authors.forename: Tomoya
authors.initials: T
authors.lastname: Fukui
authors.forename: Wu-Lin
authors.initials: WL
authors.lastname: Zuo
authors.forename: Ion Wa
authors.initials: IW
authors.lastname: Chao
authors.forename: Yael
authors.initials: Y
authors.lastname: Strulovici-Barel
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Downey
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002478:Cells, Cultured; D019743:Chemokines, CXC / Q000819:agonists / Q000235:genetics* / Q000276:immunology; D045424:Complex Mixtures / Q000302:isolation & purification / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005260:Female; D015870:Gene Expression; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology; D012137:Respiratory System / Q000276:immunology / Q000473:pathology; D012907:Smoking / Q000009:adverse effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016019:Survival Analysis
chemical_list: C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D045424:Complex Mixtures