Vitamin D receptor-binding site variants affect prostate cancer progression
Journal
Oncotarget
Journal Volume
8
Journal Issue
43
Pages
74119-74128
Date Issued
2017
Author(s)
Lin V.C.
Huang S.-P.
Ting H.-J.
Ma W.-L.
Yu C.-C.
Yin H.-L.
Huang T.-Y.
Lee C.-H.
Chang T.-Y.
Lu T.-L.
Bao B.-Y.
Abstract
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 downregulation 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. ? Lin et al.
Subjects
progression; Prostate cancer; Single nucleotide polymorphisms; Susceptibility genes; Vitamin D receptor
SDGs
Other Subjects
hemochromatosis protein; messenger RNA; small interfering RNA; vitamin D receptor; adult; advanced cancer; aged; Article; binding site; cancer growth; cancer prognosis; cell migration; cell proliferation; cohort analysis; controlled study; correlation analysis; disease course; down regulation; gene; gene expression; gene silencing; genetic database; genotype; HFE gene; human; human cell; major clinical study; male; microarray analysis; PC-3 cell line; prediction; prostate cancer; prostate cancer cell line; receptor binding; single nucleotide polymorphism; TUSC3 gene; wound healing
Publisher
Impact Journals LLC
Type
journal article