title: Vitamin A depletion induced by cigarette smoke is associated with an increase in lung cancer-related markers in rats.
abstract: BACKGROUND
  We have previously demonstrated that cigarette smoke is associated with a significant reduction of retinoic acid in rat lungs and the formation of tracheal precancerous lesions. However, the underlying mechanism of cancer risk induced by vitamin A deficiency is unclear. The purpose of this study was to determine whether the cigarette smoke-induced depletion of vitamin A is related to changes in lung cancer risk-related molecular markers.
  
  
  RESULTS
  We investigated the roles of the retinoic acid receptors (RARs) as well as other biomarkers for potential cancer risk in the lungs of rats exposed to cigarette smoke. Twenty-four male weanling rats were fed a purified diet and divided equally into four groups. Three experimental groups were exposed to increasing doses of cigarette smoke from 20, 40 or 60 commercial cigarettes/day for 5 days/week. After 6 weeks, the retinoic acid concentrations in the lung tissue as measured via high performance liquid chromatography (HPLC) significantly decreased (P < 0.01) in cigarette smoke exposed groups. Western Blot analysis revealed that cigarette smoke exposure increased lung protein expression of RAR α in a threshold manner and decreased RAR β and RAR γ expression in a dose-dependent fashion. Protein expressions of cyclin E and proliferating cell nuclear antigen (PCNA) were increased significantly in a dose-dependent manner in cigarette smoke exposed-groups. Additionally, there was a significant increase in protein expression of cJun and cyclin D1 demonstrating a threshold effect similar to that exhibited by RARα, suggesting a potential independent signaling pathway for RARα in lung carcinogenesis.
  
  
  CONCLUSIONS
  Findings from this study suggest that cigarette smoke-induced lung retinoic acid depletion may involve two independent pathways, RARα- and RARβ-mediated, responsible for the increased cancer risk associated with cigarette smoke-induced vitamin A deficiency.
authors.affiliation: Department of Human Nutrition, Kansas State University, 213 Justin Hall, Manhattan, KS, 66506, USA. Yuan.Xue@cshs.org.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Applied Health Science, Wheaton College, 501 College Avenue, Wheaton, IL, 60187, USA. Ethan.Harris@my.wheaton.edu.
authors.forename: Ethan
authors.initials: E
authors.lastname: Harris
authors.affiliation: Department of Human Nutrition, Kansas State University, 213 Justin Hall, Manhattan, KS, 66506, USA. wwang@k-state.edu.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Human Nutrition, Kansas State University, 213 Justin Hall, Manhattan, KS, 66506, USA. Richard.Baybutt@wheaton.edu.|Department of Applied Health Science, Wheaton College, 501 College Avenue, Wheaton, IL, 60187, USA. Richard.Baybutt@wheaton.edu.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Baybutt
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism* / Q000473:pathology; D014801:Vitamin A / Q000378:metabolism*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014801:Vitamin A; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C000607073:Rara protein, rat