The Yin and Yang of vitamin D receptor (VDR) signaling in neoplastic progression: Operational networks and tissue-specific growth control

摘要

class="kwd-title">Abbreviations: 1α,25-(OH)2 D3, one alpha, 25 dihydroxyvitamin D3, APC, adenomatous polyposis coli, CRC, colorectal cancer, DMBA, dimethylbenzanthracene, DR3-type, directly repeated arrangement of the hexameric binding sites with three spacing nucleotides, DRIP, Vitamin D receptor-interacting protein, ERK, extracellular signal-regulated kinase, GSK3β, glycogen synthase kinase beta, HDAC, histone deacetylator co-repressor complex, MAPK, mitogen-activated protein kinase, NCoR, nuclear receptor co-repressor, NHL, non-Hodgkins lymphoma, OPN, osteopontin, RAC3, receptor activated coactivators 3, ROCK, Rho-associated coiled kinase, RXR, retinoid X receptor, SRC-1, steroid receptor coactivators-1, Tcf, T cell factor, TIF2, transcriptional intermediary factor 2, TPA, 12-O-tetradecanoylphorbol-13-acetate, VDRE, vitamin D response element, VDR, vitamin D receptor, WINAC, Williams syndrome transcription factor (WSTF) including nucleosome assembly complex class="kwd-title">Keywords: 1α,25-(OH)2 D3, Vitamin D receptor, Signaling, Cancer class="head no_bottom_margin" id="idm140706804100816title">AbstractSubstantive evidence implicates vitamin D receptor (VDR) or its natural ligand 1α,25-(OH)2 D3 in modulation of tumor growth. However, both human and animal studies indicate tissue-specificity of effect. Epidemiological studies show both inverse and direct relationships between serum 25(OH)D levels and common solid cancers. VDR ablation affects carcinogen-induced tumorigenesis in a tissue-specific manner in model systems. Better understanding of the tissue-specificity of vitamin D-dependent molecular networks may provide insight into selective growth control by the seco-steroid, 1α,25-(OH)2 D3. This commentary considers complex factors that may influence the cell- or tissue-specificity of 1α,25-(OH)2 D3/VDR growth effects, including local synthesis, metabolism and transport of vitamin D and its metabolites, vitamin D receptor (VDR) expression and ligand-interactions, 1α,25-(OH)2 D3 genomic and non-genomic actions, Ca²⁺ flux, kinase activation, VDR interactions with activating and inhibitory vitamin D responsive elements (VDREs) within target gene promoters, VDR coregulator recruitment and differential effects on key downstream growth regulatory genes. We highlight some differences of VDR growth control relevant to colonic, esophageal, prostate, pancreatic and other cancers and assess the potential for development of selective prevention or treatment strategies.