Antioxidant response gene expression in the bronchial airway epithelial cells of smokers at risk for lung cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE19027 | GEO | 2010/10/01
SECONDARY ACCESSION(S): PRJNA120623
REPOSITORIES: GEO
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Project description:Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. This study examines the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer. We assessed global gene expression in histologically normal airway epithelial cells obtained at bronchoscopy from smokers who developed lung cancer (SC, n=20), smokers without lung cancer (SNC, n=24), and never smokers (NS, n=8). Functional enrichment showed that the NRF2-mediated antioxidant response pathway differed significantly among these groups. Keywords: Global mRNA expression profiling 21 total arrays (20 unique patients) run on total RNA obtained from Bronchial Epithelium of Smokers with Lung Cancer 30 total arrays (24 unique patients) run on total RNA obtained from Bronchial Epithelium of Smokers without Lung Cancer 9 total arrays (8 unique patients) run on total RNA obtained from Bronchial Epithelium of Never Smokers
2010-09-30 | E-GEOD-19027 | biostudies-arrayexpress
Project description:Nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) is an oxidant responsive transcription factor known to induce phase 2 detoxifying and antioxidant genes to protect cells from oxidative stress. Cigarette smoke, with its large oxidant content, is a major stressor to the small airway epithelium, the cells of which are vulnerable to oxidant damage and consequent malignant transformation. In this study, we assessed the role of cigarette smoke in activation of Nrf2 in the human small airway epithelium in vivo. Fiberoptic bronchoscopy was used to sample a pure population of small airway epithelium in 38 healthy nonsmokers and 45 healthy smokers, and gene expression was assessed using Affymetrix HG-U133 Plus 2.0 microarrays. Compared to that of healthy nonsmokers, Nrf2 protein was significantly activated in the small airway epithelium of healthy normal smokers and localized in the nucleus (p<0.05). Of the human homologs of 201 known murine Nrf2-mediated genes, 13 highly smoking-responsive genes were identified (p<10-4, all comparisons smokers to nonsmokers). Using a “Nrf2-index” to quantify the extent of expression in the small airway epithelium of these 13 known Nrf2 genes, variability in the level of expression was observed among the 45 healthy smokers, but the variability was coordinately modulated among the 13 genes, an observation confirmed by TaqMan quantitative PCR. This variability in the coordinate level of expression of the 13 Nrf2-mediated genes was independent of the smoking history. Based on these observations, the “Nrf2 index” was used to evaluate whether other genes modulated by smoking in the small airway epithelium were also coordinately up- or down- modulated among the 45 healthy smokers. Two genes, pirin (PIR) and UDP glucuronosyltransferase 1 family polypeptide A4 (UGT1A4), not previously known to be modulated by Nrf2 were identified as being coordinately modulated among the 45 smokers. Both genes contain several functional antioxidant response elements in the promoter region. Using an electrophoretic mobility shift assay, these antioxidant response elements in the promoters of PIR and UGT1A4 responded in vitro to activated Nrf2. These observations are consistent with the concept that Nrf2 plays an important role in regulating cellular defenses against smoking in the highly vulnerable small airway epithelium cell population, and that there is variability among the population in the relative Nrf2 responsiveness to a similar oxidant burden. Affymetrix arrays were used to assess gene expression data in small airway epithelium obtained by fiberoptic bronchoscopy of 38 healthy non-smokers and 45 healthy smokers
2009-07-13 | E-GEOD-11952 | biostudies-arrayexpress
Project description:Nuclear factor erythroid 2-related factor 2 (NFE2L2, Nrf2) is an oxidant responsive transcription factor known to induce phase 2 detoxifying and antioxidant genes to protect cells from oxidative stress. Cigarette smoke, with its large oxidant content, is a major stressor to the small airway epithelium, the cells of which are vulnerable to oxidant damage and consequent malignant transformation. In this study, we assessed the role of cigarette smoke in activation of Nrf2 in the human small airway epithelium in vivo. Fiberoptic bronchoscopy was used to sample a pure population of small airway epithelium in 38 healthy nonsmokers and 45 healthy smokers, and gene expression was assessed using Affymetrix HG-U133 Plus 2.0 microarrays. Compared to that of healthy nonsmokers, Nrf2 protein was significantly activated in the small airway epithelium of healthy normal smokers and localized in the nucleus (p<0.05). Of the human homologs of 201 known murine Nrf2-mediated genes, 13 highly smoking-responsive genes were identified (p<10-4, all comparisons smokers to nonsmokers). Using a “Nrf2-index” to quantify the extent of expression in the small airway epithelium of these 13 known Nrf2 genes, variability in the level of expression was observed among the 45 healthy smokers, but the variability was coordinately modulated among the 13 genes, an observation confirmed by TaqMan quantitative PCR. This variability in the coordinate level of expression of the 13 Nrf2-mediated genes was independent of the smoking history. Based on these observations, the “Nrf2 index” was used to evaluate whether other genes modulated by smoking in the small airway epithelium were also coordinately up- or down- modulated among the 45 healthy smokers. Two genes, pirin (PIR) and UDP glucuronosyltransferase 1 family polypeptide A4 (UGT1A4), not previously known to be modulated by Nrf2 were identified as being coordinately modulated among the 45 smokers. Both genes contain several functional antioxidant response elements in the promoter region. Using an electrophoretic mobility shift assay, these antioxidant response elements in the promoters of PIR and UGT1A4 responded in vitro to activated Nrf2. These observations are consistent with the concept that Nrf2 plays an important role in regulating cellular defenses against smoking in the highly vulnerable small airway epithelium cell population, and that there is variability among the population in the relative Nrf2 responsiveness to a similar oxidant burden.
2009-07-13 | GSE11952 | GEO
Project description:Cigarette smoking is the major cause of cancers of the respiratory tract, including non-small cell lung cancer (NSCLC) and head and neck cancer (HNC). In order to better understand carcinogenesis of the lung and upper airways, we have compared the gene expression profiles of tumour-distant, histologically normal bronchial biopsy specimens obtained from current smokers with NSCLC or HNC (SC, considered as a single group), as well as non-smokers (NS) and smokers without cancer (SNC). RNA from a total of 97 biopsies was used for gene expression profiling (Affymetrix HG-U133 Plus 2.0 array). Differentially expressed genes were used to compare NS, SNC, and SC, and functional analysis was carried out using Ingenuity Pathway Analysis (IPA). Smoking-related cancer of the respiratory tract was found to affect the expression of genes encoding xenobiotic biotransformation proteins, as well as proteins associated with crucial inflammation/immunity pathways and other processes that protect the airway from the chemicals in cigarette smoke or contribute to carcinogenesis. Finally, we used the prediction analysis for microarray (PAM) method to identify gene signatures of cigarette smoking and cancer, and uncovered a 15-gene signature that distinguished between SNC and SC with an accuracy of 83%. Thus, gene profiling of histologically normal bronchial biopsy specimens provided insight into cigarette-induced carcinogenesis of the respiratory tract and gene-signatures of cancer in smokers.
2014-05-24 | E-MTAB-1690 | biostudies-arrayexpress
Project description:Testican 3 (coded for by SPOCK3), is an extracellular matrix heparan/chondroitin sulphate proteoglycan that possesses serine and cysteine protease inhibitor-like domains Based on the knowledge that serine proteases contribute to the destruction of the lung in cigarette smokers, but that only a fraction of smokers develop smoking-induced lung disease, we hypothesized that smokers expressed SPOCK3 at lower levels in the small airway epithelium, the initial site of smoking-induced disease, and further, that genetic variability modulates the expression of SPOCK3 in the airway epithelium. Assessment of gene expression in the small airway epithelium (10th -12th order bronchi) of healthy non-smokers (n=38) and healthy smokers (n=42), demonstrated that the expression levels of SPOCK3 were significantly lower in healthy smokers compared to healthy nonsmokers (p<0.04). Affymetrix Human SNP array 5.0 was used to assess genome wide single nucleotide polymorphisms (SNPs) within 100 kbp of the SPOCK3 gene in the same nonsmokers and smokers, and these SNPs were correlated with small airway gene expression of SPOCK3, with correction for variation in genetic ancestry. There was a significant correlation of SPOCK3 small airway epithelial gene expression with 13 adjacent SNPs in the SPOCK3 gene (p<10-3, all comparisons, Wald test). For example, the TT allele of rs13124292, located in intron 3, was associated with a small airway epithelial expression levels of 0.56 ± 0.07, and the AA genotype with expression levels of 2.31 ± 0.26 (p<10-6, pairwise t test). Interestingly, smoking appeared to lessen the degree to which genotype associated with SPOCK3 expression level, i.e., smoking to some extent overrode the influence of genetic variation. The observation that SPOCK3 gene expression in the small airway epithelium is reduced in smokers, and that smoking interacts with cis-genomic variations to determine the levels of SPOCK3 small airway epithelial gene expression, is consistent with the concept that everyone is at risk for smoking-induced lung disease, but that inherited genetic variations contribute to the pathogenesis of susceptibility to smoking-induced disease.
2024-06-05 | GSE13932 | GEO
Project description:Rationale: Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to never-smokers. Objectives: Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. Methods: SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 10 healthy never-smokers and 10 healthy smokers, before and after they quit for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. Results: There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy never-smokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway the top enriched pathway of the target genes of the persistent deregulated miRNAs. Conclusions: In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammation diseases or lung cancer, it is likely that persistent smoking-related changes in small airway epithelium miRNAs play a role in the subsequent development of these disorders. MicroRNA profiling identified 34 miRNAs up-regulated by cigarette smoking in human small airway epithelium. Even after quitting smoking for 3 months, 12 miRNAs didnât return to normal level.
2015-11-23 | E-GEOD-53519 | biostudies-arrayexpress
Project description:Rationale: Even after quitting smoking, the risk of the development of chronic obstructive pulmonary disease (COPD) and lung cancer remains significantly higher compared to never-smokers. Objectives: Based on the knowledge that COPD and most lung cancers start in the small airway epithelium (SAE), we hypothesized that smoking modulates miRNA expression in the SAE linked to the pathogenesis of smoking-induced airway disease, and that some of these changes persist after smoking cessation. Methods: SAE was collected from 10th to 12th order bronchi using fiberoptic bronchoscopy. Affymetrix miRNA 2.0 arrays were used to assess miRNA expression in the SAE from 10 healthy never-smokers and 10 healthy smokers, before and after they quit for 3 months. Smoking status was determined by urine nicotine and cotinine measurement. Results: There were significant differences in the expression of 34 miRNAs between healthy smokers and healthy never-smokers (p<0.01, fold-change >1.5), with functions associated with lung development, airway epithelium differentiation, inflammation and cancer. After quitting smoking for 3 months, 12 out of the 34 miRNAs did not return to normal levels, with Wnt/β-catenin signaling pathway the top enriched pathway of the target genes of the persistent deregulated miRNAs. Conclusions: In the context that many of these persistent smoking-dependent miRNAs are associated with differentiation, inflammation diseases or lung cancer, it is likely that persistent smoking-related changes in small airway epithelium miRNAs play a role in the subsequent development of these disorders.
2015-11-23 | GSE53519 | GEO
Project description:The initial site of smoking-induced lung disease is the small airway epithelium, which is difficult and time consuming to sample by fiberoptic bronchoscopy. We developed a rapid, office-based procedure to obtain trachea epithelium without conscious sedation from healthy nonsmokers (n=26) and healthy smokers (n=19, 27 ± 15 pack-yr). Gene expression differences [fold-change >1.5, p< 0.01, Benjamini-Hochberg correction] were assessed with Affymetrix microarrays. 1,057 probe sets were differentially expressed in healthy smokers vs nonsmokers, representing >500 genes. Trachea gene expression was compared to an independent group of small airway epithelial samples (n=23 healthy nonsmokers, n=19 healthy smokers, 25 ± 12 pack-yr). The trachea epithelium is more sensitive to smoking, responding with 3-fold more differentially-expressed genes than small airway epithelium. The trachea transcriptome paralleled the small airway epithelium, with 156 of 167 (93%) genes that are significantly up- and down-regulated by smoking in the small airway epithelium showing similar direction and magnitude of response to smoking in the trachea. Trachea epithelium can be obtained without conscious sedation, representing a less invasive surrogate “canary” for smoking-induced changes in the small airway epithelium. This should prove useful in epidemiologic studies correlating gene expression with clinical outcome in assessing smoking-induced lung disease. Experiment Overall Design: Tracheal gene expression: matched group of small airway epithelial samples (n=23 healthy non-smokers, n= 19 healthy smokers)
2009-09-04 | E-GEOD-13933 | biostudies-arrayexpress
Project description:The aldokatoreductases (AKRs) represent a gene superfamily that code for monomeric, soluble NAD(P)H-dependent oxidoreductases that mediate elimination reactions. AKR1B10, an AKR that functions to eliminate retinals, has been observed to be upregulated in squamous metaplasma and non small cell lung cancer, and has been suggested as a diagnostic marker specific to tobacco-related carcinogenesis. In the context of the link of smoking and lung cancer and the enhanced expression of AKR1B10 expression in lung cancer, we hypothesize that enhanced expression of AKR1B10 may be initiated in healthy smokers, prior to the development of any evidence of lung cancer. For this purpose, expression of AKR1B10 was assessed at the mRNA level using microarrays in the large airway epithelium (21 healthy nonsmokers, 31 health smokers) and small airway epithelium (51 healthy nonsmokers, 58 healthy smokers) obtained by fiberoptic bronchoscopy and brushing, as well as assessment in a subset of this population by TaqMan PCR and in endobronchial biopsies by Western analysis and immunohistochemistry. Compared to healthy nonsmokers, ARK1B10 mRNA levels were markedly upregulated in both the large and small airway epithelium of healthy smokers (large airway microarray p<0.0001, small airway p<0.0001; TaqMan large airway, p<0.02, small airway p<0.01). Consistent with the mRNA data, AKR1B10 protein was significantly upregulated in the airway epithelium of healthy smokers as assessed by Western analysis and by immunohistochemistry, with AKR1B10 expressed in both differentiated and basal cells of the normal epithelium. Finally, cigarette smoke extract mediated up-regulation of AKR1B10 in airway epithelial cells in vitro. Thus, smoking per se mediates up-regulation of AKR1B10 expression in the airway epithelium of healthy smokers with no evidence of lung cancer. In the context of these observations, and the link of AKR1B10 to the metabolism of retinals and to lung cancer, the smoking-induced up-regulation of AKR1B10 may be an early process in the multiple events leading to the develop of lung cancer.
2017-08-25 | GSE18385 | GEO
Project description:Modification of Gene Expression of the Small Airway Epithelium in Response to Cigarette Smoking The earliest morphologic evidence of changes in the airways associated with chronic cigarette smoking is in the small airways. To help understand how smoking modifies small airway structure and function, we developed a strategy using fiberoptic bronchoscopy and brushing to sample the human small airway (10th-12th order) bronchial epithelium to assess gene expression (HG-133 Plus 2.0 array) in phenotypically normal smokers (n=10, 33 ± 7 pack-yr) compared to matched non-smokers (n=12). Even though the smokers were phenotypically normal, analysis of the small airway epithelium of the smokers compared to the non-smokers demonstrated up- and -down-regulation of genes in multiple categories relevant to the pathogenesis of chronic obstructive lung disease (COPD), including genes coding for cytokines/innate immunity, apoptosis, mucin, response to oxidants and xenobiotics, and general cellular processes. In the context that COPD starts in the small airways, these gene expression changes in the small airway epithelium in phenotypically normal smokers are candidates for the development of therapeutic strategies to prevent the onset of COPD. Keywords: smokers vs non-smokers
2006-11-21 | GSE4498 | GEO