In addition, we observed elevated vitamin D receptor (VDR) mRNA and protein levels in both LNCaP and MCF-7 cells following the exposure of the two cell lines to BGP-13.
Pathway analyses found that the set of SNPs that included all seven genes (P = .008) as well as sets of SNPs that included VDR (P = .01) and CYP27A1 (P = .02) were associated with risk of lethal prostate cancer.
Recent studies suggest variation in genes along the vitamin D pathway, as well as vitamin D receptor (VDR) protein levels, may be associated with prostate cancer.
These findings indicate that the PC-susceptibility locus represented by rs12653946 at 5p15 is likely to regulate IRX4 expression in prostate which could suppress PC growth by interacting with the VDR pathway, conferring to PC susceptibility.
DC-SCRIPT is a key regulator of nuclear receptors AR and VDR that play an opposite role in prostate cancer etiology and loss of DC-SCRIPT may be involved in the onset of prostate cancer.
We also examined vitamin D related genes, VDR and CYP27B1, and found a significant association of PCa with the TaqI polymorphism (rs731236) in the former.
Our main findings are that 1,25D regulates PTHrP levels via multiple pathways in PC-3 and C4-2 (human prostate cancer) cell lines, and regulation is dependent on VDR expression.
High VDR expression in prostate tumors is associated with a reduced risk of lethal cancer, suggesting a role of the vitamin D pathway in prostate cancer progression.
Three VDR tagSNPs (rs3782905, rs7299460, and rs11168314), one CYP27B1 tagSNP (rs3782130), and five CYP24A1 tagSNPs (rs3787557, rs4809960, rs2296241, rs2585428, and rs6022999) significantly altered risks of PCa death.
The loss of anti-proliferative responsiveness in prostate cancer cell lines toward ligands for vitamin D receptor, retinoic acid receptors/retinoid X receptors and peroxisome proliferator activated receptor (PPAR)alpha/gamma may entail underlying epigenetic events, as ligand insensitivity reflects significantly altered messenger RNA expression of corepressors and histone-modifying enzymes.
Also VDR gene, that is a component of ligand (steroid)-dependent nuclear transcription factor superfamily, shows various polymorphisms which appear to be associated with PC risk.
The active metabolite of vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] acting through the vitamin D receptor decreases prostate cancer cell growth and invasiveness.
Although most studies to date have examined only a few VDR polymorphisms, more are beginning to comprehensively investigate polymorphisms in the VDR as well as in other vitamin D pathway genes, such as the vitamin D-binding protein gene (Gc) and CYP27B1 and CYP24A1, which code for enzymes that, respectively, synthesize and degrade 1alpha,25-(OH)(2)-vitamin D. Currently, there is no strong, consistent epidemiologic evidence for substantial influences of single variants in vitamin D pathway genes on risk for colorectal, breast, or prostate cancer, but promising leads are developing.
Most of the inconsistent results have been reported in studies investigating the vitamin D receptor gene polymorphism in association with prostate cancer.