title: A functional variant in miR-143 promoter contributes to prostate cancer risk.
abstract: MicroRNAs are important regulators in numerous cellular processes, including cell differentiation, proliferation, and apoptosis. Recently, miR-143 was identified as a tumor suppressor in prostate cancer (PCa). To explore the mechanism of dysregulation and anti-tumor function of miR-143 in PCa, we first found a single-nucleotide polymorphism rs4705342T>C in the promoter region of miR-143 through bioinformatics tools and then performed a case-control study including 608 PCa patients and 709 controls. Results suggested that subjects with TC/CC genotypes had significantly decreased risk of PCa compared with those with TT genotype (adjusted OR 0.68, 95 % CI 0.55-0.85). Further functional assays showed that the risk-associated T allele increased the protein-binding affinity and reduced the activity of the promoter compared with C allele. In addition, restoration of miR-143 by mimics in PCa cells significantly inhibited cell proliferation and migration and down-regulated the expression level of kallikrein-related peptidase 2 (KLK2) mRNA and protein. The miR-143-KLK2 axis was also confirmed by luciferase reporter assay in vitro. In conclusion, our findings demonstrate that there is the significant association between the functional promoter variant rs4705342T>C in miR-143 and PCa risk and newly describe the miR-143-KLK2 interaction which provided another potential mechanism for miR-143 anti-tumor function.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 818 East Tianyuan Road, Nanjing, 211166, China.|Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.|Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.|Orthopaedic Institute, Soochow University, Suzhou, China.
authors.forename: Dongyan
authors.initials: D
authors.lastname: Zhong
authors.affiliation: Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.|Department of Public Health, Jiangxi Center for Disease Control and Prevention, 555 Beijing East Road, Nanchang, 330029, Jiangxi, China.
authors.forename: Jialin
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.|Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.|Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Tong
authors.affiliation: Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qin
authors.affiliation: Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 818 East Tianyuan Road, Nanjing, 211166, China. drzdzhang@gmail.com.|Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China. drzdzhang@gmail.com.|Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China. drzdzhang@gmail.com.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 818 East Tianyuan Road, Nanjing, 211166, China. mwang@njmu.edu.cn.|Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China. mwang@njmu.edu.cn.|Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China. mwang@njmu.edu.cn.
authors.forename: Meilin
authors.initials: M
authors.lastname: Wang
mesh_terms: D000368:Aged; D044466:Asian People / Q000235:genetics; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007610:Kallikreins / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C542359:MIRN143 microRNA, human; D035683:MicroRNAs; C000595667:KLK2 protein, human; D007610:Kallikreins
keywords: Genetic susceptibility; KLK2; Molecular epidemiology; Prostate cancer; miR-143