Characterization of vitamin D receptor (VDR) in lung adenocarcinoma

Purpose: The anti-proliferative effects of 1 alpha,25-dihydroxyvitamin D-3 (1,25-D-3, calcitriol, the active form of vitamin D) are mediated by the nuclear vitamin D receptor (VDR). In the present study, we characterized VDR expression in lung adenocarcinoma (AC). Experimental design: We examined VDR mRNA expression using a quantitative real-time PCR (qRT-PCR) in 100 patients who underwent surgery for lung AC. In a subset of these patients (n=89), we examined VDR protein expression using immunohistochemistry. We also examined the association of VDR protein expression with circulating serum levels of 25-hydroxyvitamin D-3 (25-D-3) and 1,25-D-3. The antiproliferative effects and cell cycle arrest of 1,25-D-3 were examined using lung cancer cell lines with high (SKLU-1) as well as low (A549) expression of VDR mRNA. Results: Higher VDR expression correlates with longer survival after adjusting for age, sex, disease stage and tumor grade (HR 0.73, 95% CI 0.58-0.91). In addition, there was a positive correlation (r=0.38) between serum 1,25-D-3 and tumor VDR protein expression. A greater anti-proliferative effect of 1,2503 was observed in high compared to low VDR-expressing cell lines; these effects corresponded to G1 cell cycle arrest; this was associated with a decline in cyclin D1, S-phase kinase protein 2 (Skp2), retinoblastoma (Rb) and minichromosome maintenance 2 (MCM2) proteins involved in S-phase entry. Conclusions: Increased VDR expression in lung AC is associated with improved survival. This may relate to a lower proliferative status and G1 arrest in high VDR-expressing tumors. Published by Elsevier Ireland Ltd.