title: Down-regulation of the canonical Wnt β-catenin pathway in the airway epithelium of healthy smokers and smokers with COPD.
abstract: BACKGROUND
  The Wnt pathway mediates differentiation of epithelial tissues; depending on the tissue types, Wnt can either drive or inhibit the differentiation process. We hypothesized that key genes in the Wnt pathway are suppressed in the human airway epithelium under the stress of cigarette smoking, a stress associated with dysregulation of the epithelial differentiated state.
  
  
  RESULTS
  Microarrays were used to assess the expression of Wnt-related genes in the small airway epithelium (SAE) obtained via bronchoscopy and brushing of healthy nonsmokers, healthy smokers, and smokers with COPD. Thirty-three of 56 known Wnt-related genes were expressed in the SAE. Wnt pathway downstream mediators β-catenin and the transcription factor 7-like 1 were down-regulated in healthy smokers and smokers with COPD, as were many Wnt target genes. Among the extracellular regulators that suppress the Wnt pathway, secreted frizzled-related protein 2 (SFRP2), was up-regulated 4.3-fold in healthy smokers and 4.9-fold in COPD smokers, an observation confirmed by TaqMan Real-time PCR, Western analysis and immunohistochemistry. Finally, cigarette smoke extract mediated up-regulation of SFRP2 and down-regulation of Wnt target genes in airway epithelial cells in vitro.
  
  
  CONCLUSIONS
  Smoking down-regulates the Wnt pathway in the human airway epithelium. In the context that Wnt pathway plays an important role in differentiation of epithelial tissues, the down-regulation of Wnt pathway may contribute to the dysregulation of airway epithelium differentiation observed in smoking-related airway disorders.
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Joumana
authors.initials: J
authors.lastname: Ahmed
authors.forename: Guoqing
authors.initials: G
authors.lastname: Wang
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Hassan
authors.forename: Yael
authors.initials: Y
authors.lastname: Strulovici-Barel
authors.forename: Neil R
authors.initials: NR
authors.lastname: Hackett
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012907:Smoking / Q000009:adverse effects*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D008565:Membrane Proteins; D014028:Tobacco Smoke Pollution; D051153:Wnt Proteins; D051176:beta Catenin; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins