Smoking-induced upregulation of AKR1B10 expression in the airway epithelium of healthy individuals.
BACKGROUND
The aldo-keto reductase (AKR) gene superfamily codes for monomeric, soluble reduced nicotinamide adenine dinucleotide phosphate-dependent oxidoreductases that mediate elimination reactions. AKR1B10, an AKR that eliminates retinals, has been observed as upregulated in squamous metaplasia and non-small cell lung cancer and has been suggested as a diagnostic marker specific to tobacco-related carcinogenesis. We hypothesized that upregulation of AKR1B10 expression may be initiated in healthy smokers prior to the development of evidence of lung cancer.


METHODS
Expression of AKR1B10 was assessed at the mRNA level using microarrays with TaqMan confirmation in the large airway epithelium (21 healthy nonsmokers, 31 healthy smokers) and small airway epithelium (51 healthy nonsmokers, 58 healthy smokers) obtained by fiberoptic bronchoscopy and brushing.


RESULTS
Compared with healthy nonsmokers, AKR1B10 mRNA levels were significantly upregulated in both large and small airway epithelia of healthy smokers. Consistent with the mRNA data, AKR1B10 protein was significantly upregulated in the airway epithelium of healthy smokers as assessed by Western blot analysis and immunohistochemistry, with AKR1B10 expressed in both differentiated and basal cells. Finally, cigarette smoke extract mediated upregulation of AKR1B10 in airway epithelial cells in vitro, and transfection of AKR1B10 into airway epithelial cells enhanced the conversion of retinal to retinol.


CONCLUSIONS
Smoking per se mediates upregulation of AKR1B10 expression in the airway epithelia 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 upregulation of AKR1B10 may be an early process in the multiple events leading to lung cancer.
Wang
Rui
R
Department of Genetic Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
Wang
Guoqing
G
Ricard
Megan J
MJ
Ferris
Barbara
B
Strulovici-Barel
Yael
Y
Salit
Jacqueline
J
Hackett
Neil R
NR
Gudas
Lorraine J
LJ
Crystal
Ronald G
RG
D000328:Adult; D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism*; D000074408:Aldo-Keto Reductases; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001999:Bronchoscopy; D002478:Cells, Cultured; D015331:Cohort Studies; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D040081:Protein Array Analysis; D012333:RNA, Messenger / Q000032:analysis; D012016:Reference Values; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*; D015854:Up-Regulation
D015415:Biomarkers; D012333:RNA, Messenger; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase