Chest
Volume 138, Issue 6, December 2010, Pages 1402-1410
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Original Research
Lung Cancer
Smoking-Induced Upregulation of AKR1B10 Expression in the Airway Epithelium of Healthy Individuals

https://doi.org/10.1378/chest.09-2634Get rights and content

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.

Section snippets

Study Population

All subjects were recruited through advertisements in local newspapers, on electronic bulletin boards, and through an ongoing program of free spirometry screening. The evaluation of all individuals was performed at the Department of Genetic Medicine Clinical Research Facility under the auspices of the Weill Cornell National Institutes of Health Clinical Translational Science Center (New York, NY), using Institutional Review Board-approved clinical protocols. Nonsmokers and smokers were

Study Population

A total of 52 large airway samples from 21 healthy nonsmokers and 31 healthy smokers and 109 small airway samples from 51 healthy nonsmokers and 58 healthy smokers were analyzed on Affymetrix HG-U133 Plus 2.0 microarrays (Table 1). For the large airway samples, there were no differences between groups with regard to ancestral background (P > .4), sex (P > .1), and age (P > .2). For the small airway samples, there also were no differences between groups with regard to ancestral background (P >

Discussion

AKR1B10, a member of the AKR family, has been suggested as an early detection marker and treatment target for NSCLC.12 Using microarray analysis to compare gene expression of the airway epithelium in healthy smokers and healthy nonsmokers, we found AKR1B10 was highly upregulated in both large and small airway epithelia of healthy smokers. The microarray data were confirmed at both the mRNA level (TaqMan real-time PCR) and the protein level (Western blot analysis and immunohistochemistry).

Acknowledgments

Author Contributions: Dr R. Wang: contributed to the background research, experimental design, execution and data analysis, TaqMan real-time PCR, in vitro MTT assay, and writing the manuscript.

Dr G. Wang: performed experimental work, including Western analysis.

Ms Ricard: contributed to the retinoic acid experiments.

Ms Ferris: performed experimental work related to immunohistochemistry.

Ms Strulovici-Barel: contributed to compilation and analysis of microarray data.

Ms Salit: contributed to

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    Funding/Support: This study was supported, in part, by the National Institutes of Health [R01 HL074326, P50 HL084936, UL1-RR024996, T32 HL094284] and the National Cancer Institute [R01CA097543].

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).

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