Research Papers:
Vitamin D receptor-binding site variants affect prostate cancer progression
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Abstract
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
1Department of Urology, E-Da Hospital, Kaohsiung 824, Taiwan
2School of Medicine for International Students, I-Shou University, Kaohsiung 840, Taiwan
3Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
4Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
5Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
6Department of Biological Sciences and Technology, National University of Tainan, Tainan 700, Taiwan
7Graduate Institution of Clinical Medical Science, and Graduate Institution of Cancer Biology, China Medical University, Taichung 404, Taiwan
8Sex Hormone Research Center, China Medical University Hospital, Taichung 404, Taiwan
9Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
10Department of Urology, School of Medicine, National Yang-Ming University, Taipei 112, Taiwan
11Department of Pharmacy, Tajen University, Pingtung 907, Taiwan
12Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan
13Department of Urology, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu 300, Taiwan
14Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
15Department of Pathology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
16Department of Occupational Safety and Health, China Medical University, Taichung 404, Taiwan
17Department of Pharmacy, China Medical University, Taichung 404, Taiwan
18Department of Nursing, Asia University, Taichung 413, Taiwan
Correspondence to:
Bo-Ying Bao, email: [email protected]
Keywords: progression, prostate cancer, single nucleotide polymorphisms, vitamin D receptor, susceptibility genes
Received: April 04, 2017 Accepted: May 15, 2017 Published: May 26, 2017
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 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.
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