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.
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Acknowledgments
This study was partly supported by National Natural Science Foundation of China (81230068, and 81102089), Natural Science Foundation of Jiangsu Province (BK2011773), the Key Program for Basic Research of Jiangsu Provincial Department of Education (11KJB330002 and 12KJA330002), Jiangsu Provincial Six Talent Peaks Project (2012-SWYY-028), Specialized Research Fund for the Doctoral Program of Higher Education (20123234110001), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).
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Haiyan Chu, Dongyan Zhong, and Jialin Tang have contributed equally to this work.
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Chu, H., Zhong, D., Tang, J. et al. A functional variant in miR-143 promoter contributes to prostate cancer risk. Arch Toxicol 90, 403–414 (2016). https://doi.org/10.1007/s00204-014-1396-2
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DOI: https://doi.org/10.1007/s00204-014-1396-2