Journal
ARCHIVES OF TOXICOLOGY
Volume 90, Issue 2, Pages 403-414Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00204-014-1396-2
Keywords
miR-143; Prostate cancer; KLK2; Genetic susceptibility; Molecular epidemiology
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Funding
- National Natural Science Foundation of China [81230068, 81102089]
- Natural Science Foundation of Jiangsu Province [BK2011773]
- Key Program for Basic Research of Jiangsu Provincial Department of Education [11KJB330002, 12KJA330002]
- Jiangsu Provincial Six Talent Peaks Project [2012-SWYY-028]
- Specialized Research Fund for the Doctoral Program of Higher Education [20123234110001]
- Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine)
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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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