Characterization of vitamin D receptor (VDR) in lung adenocarcinoma

Abstract

Purpose The anti-proliferative effects of 1α,25-dihydroxyvitamin D3 (1,25-D3, 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 D3 (25-D3) and 1,25-D3. The antiproliferative effects and cell cycle arrest of 1,25-D3 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-D3 and tumor VDR protein expression. A greater anti-proliferative effect of 1,25-D3 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.

Serum vitamin D, vitamin D binding protein, and lung cancer survival

“…Lung tissue expresses both 1α-hydroxylase, the enzyme that converts 25(OH)D to the metabolically active 1,25-hydroxyvitamin D (1,25(OH) 2 D) (31), and the vitamin D receptor (VDR) which mediates the anti-proliferative and other effects of 1,25(OH) 2 D (32). Furthermore, experimental studies have observed that higher VDR expression in lung tumors is associated with improved survival (33) and that vitamin D inhibits metastasis and angiogenesis in lung cancer cells (4, 5). Select characteristics of the ATBC cohort may have contributed to the weak findings observed in the current study as well as a previous analysis in ATBC of serum 25(OH)D concentration and risk of lung cancer (23).…”

Predicted 25(OH)D Score and Colorectal Cancer Risk According to Vitamin D Receptor Expression

“…For this study we measured the nuclear VDR expression level in colorectal cancer tissue because VDR modulates genomic transcription in cell nuclei (1, 7) and the nuclear VDR level—not the cytoplasmic VDR level—has been a prognostic marker of improved survival (20, 21). We retrieved formalin-fixed paraffin-embedded colorectal cancer tissue blocks from hospitals throughout the United States where colorectal cancer patients had undergone surgical resection.…”

DNA methylation profile and expression of surfactant protein A2 gene in lung cancer

“…While PEA3 plays a key role in metastasis of lung cancer cells, an increase in VDR expression in lung cancer has been associated with improved survival in patients with AC (58, 59). Moreover, associations between VDR and surfactant physiology have been previously described.…”