The loss of retinoic acid receptor alpha, beta and alcohol dehydrogenase3 expression in non-small cell lung cancer.

Abstract

The reason for unsuccessful retinoid chemoprevention of lung cancer is obscure. Therefore we examined the retinoid-related receptor expression and the tissue distribution as well as the possible interaction between retinoid-related receptor expression and cigarette smoke. Using semiquantitative conventional reverse transcriptase polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR, in situ hybridization and immunostaining, we evaluated the expression and the distribution of retinoic acid receptor alpha, beta, gamma, retinoid X receptor alpha, beta, gamma, thyroid hormone receptor alpha, beta, and alcohol dehydrogenase3 (a well-characterized retinoic acid responsive gene) in malignant and non-malignant tissues obtained from patients with non-small cell lung cancer. We also assessed the response of the bronchial epithelial cell line, BEAS-2B, following exposure to cigarette smoke extract. Compared with non-malignant tissues, malignant tissues had a 45% (P < 0.02) reducion in retinoic acid receptor alpha and beta expression, while other receptors were not affected. The expression of the alcohol dehydrogenase3 gene in malignant tissue was 50% of that observed in non-malignant tissue (P < 0.05). There was a significant correlation between the retinoic acid receptor beta-mRNA level and the alcohol dehydrogenase3-mRNA level (r = 0.52, P < 0.05). In situ hybridization and immunostaining demonstrated that retinoic acid receptor alpha and beta were localized in the airway and alveolar epithelial cells and their expression was diminished to 30% in malignant tissues compared to non-malignant tissues (P < 0.05). Interestingly, cigarette smoke extract decreased retinoic acid receptor beta mRNA in BEAS-2B cells (P < 0.05). The present findings suggest a possible association of the loss of retinoic acid receptor alpha, beta and alcohol dehydrogenase3 with lung carcinogenesis.