Prostate surgery outcomes vary with Vitamin D Receptors– May 2017

Vitamin D receptor-binding site variants affect prostate cancer progression

Oncotarget doi: 10.18632/oncotarget.18271

chance of surviving surgery

One of many graphs in the PDF
    50% chance of no follow-on Prostate Cancer
    CC = 22 months    TT = 100 months

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Victor C. Lin1,2, Shu-Pin Huang3,4,5, Huei-Ju Ting6, Wen-Lung Ma7,8, Chia-Cheng Yu9,10,11, Chao-Yuan Huang12,13, Hsin-Ling Yin14,15, Tsung-Yi Huang3, Cheng-Hsueh Lee3,5, Ta-Yuan Chang16, Te-Ling Lu17 and Bo-Ying Bao8,17,18

Vitamin D is an important modulator of cellular proliferation through the vitamin D receptor (VDR) that binds to DNA in the regulatory sequences of target genes. We hypothesized that single nucleotide polymorphisms (SNPs) in VDR-binding sites might affect target gene expression and influence the progression of prostate cancer. Using a genome-wide prediction database, 62 SNPs in VDR-binding sites were selected for genotyping in 515 prostate cancer patients and the findings were replicated in an independent cohort of 411 patients. Prognostic significance on prostate cancer progression was assessed by Kaplan-Meier analysis and the Cox regression model. According to multivariate analyses adjusted for known predictors, HFE rs9393682 was found to be associated with disease progression for localized prostate cancer, and TUSC3 rs1378033 was associated with progression for advanced prostate cancer in both cohorts. Vitamin D treatment inhibited HFE mRNA expression, and down-regulation of HFE by transfecting small interfering RNA suppressed PC-3 human prostate cancer cell proliferation and wound healing ability. In contrast, vitamin D treatment induced TUSC3 expression, and silencing TUSC3 promoted prostate cancer cell growth and migration. Further analysis of an independent microarray dataset confirmed that low TUSC3 expression correlated with poor patient prognosis. Our results warrant further studies using larger cohorts. This study identifies common variants in VDR-binding sites as prognostic markers of prostate cancer progression and HFE and TUSC3 as plausible susceptibility genes.

INTRODUCTION
Epidemiological studies have demonstrated that low sunlight exposure and poor vitamin D status at higher latitudes account for an elevated risk of a number of cancers, including prostate cancer [1, 2]. Vitamin D can be obtained from the diet; however, it is majorly synthesized in the skin using solar irradiation. The biologically active form of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25-VD), is produced by 25-hydroxylase in the liver, followed by 1α-hydroxylase in the kidney. The actions of 1,25-VD are mediated by the vitamin D receptor (VDR), a ligand-activated transcription factor. Upon activation by 1,25-VD, VDR forms a heterodimer with the retinoid X receptor, and binds to vitamin D response elements (VDREs) in the promoters of vitamin D-responsive genes [3]. Prostate cells express VDR and vitamin D metabolizing enzymes, and can respond to 1,25-VD. A volume of data supports multipronged effects of 1,25-VD in the prevention of prostate cancer progression by induction of detoxifying enzymes [4], cell cycle arrest [5], and apoptosis [6], as well as inhibition of prostate cancer cell invasion [7] and angiogenesis [8].
Genetic variants in VDREs may affect VDR-VDRE interactions, thereby resulting in altered expression of target genes and consequent cancer progression. However, no study to date has investigated the single nucleotide polymorphisms (SNPs) in VDR binding sites and their relationship to the clinical outcomes of prostate cancer. Accordingly, we conducted a two-stage study to evaluate the associations of VDRE SNPs with prostate cancer progression, and further assessed the functional relevance of candidate genes of interest, as illustrated in Supplementary Figure 1.

RESULTS
The clinical characteristics of patients in the discovery and replication cohorts and the association with disease progression are shown in Table 1. For localized prostate cancer, 45 (30.0%) and 75 (43.9%) patients experienced disease progression after radical prostatectomy (RP) during the median follow-up of 23 and 30 months in the discovery and replication cohorts, respectively. Prostate-specific antigen (PSA) at diagnosis, pathologic Gleason score, and pathologic stage were significantly associated with cancer progression in both cohorts. In the advanced prostate cancer group, 271 (74.5%) and 180 (75.3%) patients had disease progression after androgen deprivation therapy (ADT) during the median follow-up of 61 and 57 months in the discovery and replication cohorts, respectively. PSA at ADT initiation, and PSA nadir were significantly associated with cancer progression in both cohorts. Gleason score, clinical stage at diagnosis, and treatment modality were also associated with progression in the discovery cohort, but only weakly associated in the replication cohort.