Abstract
BackgroundWe 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.ResultsWe 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.ConclusionsFindings 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.
Highlights
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
A research group at Tufts University found that when ferrets, having β-carotene metabolism similar to humans, were supplemented with β-carotene and exposed to cigarette smoke, lung concentration of retinoic acid was reduced as was Retinoic Acid Receptor (RAR)-β expression, but cell proliferation markers were elevated [2]
Expressions of RARβ and RAR γ were decreased in lungs exposed to cigarette smoke The expression of RARβ was significantly reduced by more than 50 % in the group that was exposed to one pack of cigarettes and undetectable in the other two cigarette smoke-treated groups using Western blot analysis
Summary
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. 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. Understanding the mechanisms of cigarette smoke-induced lung cancer is an important area of research. A research group at Tufts University found that when ferrets, having β-carotene metabolism similar to humans, were supplemented with β-carotene and exposed to cigarette smoke, lung concentration of retinoic acid was reduced as was RAR-β expression, but cell proliferation markers were elevated [2]. To our knowledge no one has determined the effect of increased doses of cigarette smoke on lung retinoic acid and lung cancer risk-related molecular markers using a rat model
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