Vitamin A depletion induced by cigarette smoke is associated with an increase in lung cancer-related markers in rats



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Citation: Xue, Y., Harris, E., Wang, W. Q., & Baybutt, R. C. (2015). Vitamin A depletion induced by cigarette smoke is associated with an increase in lung cancer-related markers in rats. Journal of Biomedical Science, 22, 9. doi:10.1186/s12929-015-0189-0
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 alpha in a threshold manner and decreased RAR beta and RAR gamma 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 RAR alpha, suggesting a potential independent signaling pathway for RAR alpha in lung carcinogenesis. Conclusions: Findings from this study suggest that cigarette smoke-induced lung retinoic acid depletion may involve two independent pathways, RAR alpha- and RAR beta-mediated, responsible for the increased cancer risk associated with cigarette smoke-induced vitamin A deficiency.


Carcinogenesis, Rar Alpha, Rar Beta, Cjun, Pcna, Cyclin