CEBPG transcription factor correlates with antioxidant and DNA repair genes in normal bronchial epithelial cells but not in individuals with bronchogenic carcinoma.
BACKGROUND
Cigarette smoking is the primary cause of bronchogenic carcinoma (BC), yet only 10-15% of heavy smokers develop BC and it is likely that this variation in risk is, in part, genetically determined. We previously reported a set of antioxidant genes for which transcript abundance was lower in normal bronchial epithelial cells (NBEC) of BC individuals compared to non-BC individuals. In unpublished studies of the same NBEC samples, transcript abundance values for several DNA repair genes were correlated with these antioxidant genes. From these data, we hypothesized that antioxidant and DNA repair genes are co-regulated by one or more transcription factors and that inter-individual variation in expression and/or function of one or more of these transcription factors is responsible for inter-individual variation in risk for BC.


METHODS
The putative transcription factor recognition sites common to six of the antioxidant genes were identified through in silico DNA sequence analysis. The transcript abundance values of these transcription factors (n = 6) and an expanded group of antioxidant and DNA repair genes (n = 16) were measured simultaneously by quantitative PCR in NBEC of 24 non-BC and 25 BC individuals.


RESULTS
CEBPG transcription factor was significantly (p < 0.01) correlated with eight of the antioxidant or DNA repair genes in non-BC individuals but not in BC individuals. In BC individuals the correlation with CEBPG was significantly (p < 0.01) lower than that of non-BC individuals for four of the genes (XRCC1, ERCC5, GSTP1, and SOD1) and the difference was nearly significant for GPX1. The only other transcription factor correlated with any of these five target genes in non-BC individuals was E2F1. E2F1 was correlated with GSTP1 among non-BC individuals, but in contrast to CEBPG, there was no significant difference in this correlation in non-BC individuals compared to BC individuals.


CONCLUSIONS
We conclude that CEBPG is the transcription factor primarily responsible for regulating transcription of key antioxidant and DNA repair genes in non-BC individuals. Further, we conclude that the heavy smokers selected for development of BC are those who have sub-optimal regulation of antioxidant and DNA repair genes by CEBPG.
Mullins
D'Anna N
DN
Department of Medicine, Medical University of Ohio, Room 0012 Ruppert Health Building, Toledo, OH 43614, USA. damullins@meduohio.edu
Crawford
Erin L
EL
Khuder
Sadik A
SA
Hernandez
Dawn-Alita
DA
Yoon
Youngsook
Y
Willey
James C
JC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000975:Antioxidants / Q000378:metabolism*; D001665:Binding Sites; D001980:Bronchi / Q000166:cytology* / Q000378:metabolism; D001984:Bronchial Neoplasms / Q000235:genetics / Q000378:metabolism*; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004720:Endonucleases / Q000096:biosynthesis; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005979:Glutathione Peroxidase / Q000096:biosynthesis; D051549:Glutathione S-Transferase pi / Q000096:biosynthesis; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009687:Nuclear Proteins / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012737:Sex Factors; D012907:Smoking; D013482:Superoxide Dismutase / Q000096:biosynthesis; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000096:biosynthesis; D014158:Transcription, Genetic; D000076105:X-ray Repair Cross Complementing Protein 1; D000094765:Glutathione Peroxidase GPX1; D000099250:DNA Excision Repair Protein ERCC-5
D000975:Antioxidants; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005979:Glutathione Peroxidase; D051549:Glutathione S-Transferase pi; D009687:Nuclear Proteins; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors; D000076105:X-ray Repair Cross Complementing Protein 1; D000094765:Glutathione Peroxidase GPX1; D000099250:DNA Excision Repair Protein ERCC-5; C405462:CCAAT-enhancer-binding protein-gamma; C000606290:SOD1 protein, human; C000619371:XRCC1 protein, human; C496556:GSTP1 protein, human; C000722067:GPX1 protein, human