Functional polymorphisms in the promoter region of miR-17-92 cluster are associated with a decreased risk of colorectal cancer

Abstract

miR-17-92 cluster is identified as a potential oncogenic miRNA. The aim of this study was to investigate the association of polymorphisms in the promoter region of miR-17-92 cluster with the risk of colorectal cancer (CRC). Three polymorphisms (i.e., rs9588884, rs982873 and rs1813389) in the promoter of miR-17-92 were analyzed among 874 cases and 1132 controls using a TaqMan allelic discrimination assay or a polymerase chain reaction-restriction fragment length polymorphism method. Relative expression of miR-17-92 was examined among CRC tumors and noncancerous tissues using quantitative reverse transcription-PCR. Transcriptional activities were measured using dual-luciferase reporter assay. We found a significantly reduced CRC risk with the rs9588884 (GG vs. CC: adjusted OR = 0.46, 95% CI, 0.35-0.62; dominant model: adjusted OR = 0.72, 95% CI, 0.59-0.86; recessive model: adjusted OR = 0.53, 95% CI, 0.40-0.69) and the rs982873 (CC vs. TT: adjusted OR = 0.60, 95%CI, 0.46-0.80; recessive model: adjusted OR = 0.62, 95% CI, 0.49-0.80). Haplotype analysis showed that the GCG haplotype had a decreased risk for CRC compared to the CTA haplotype (adjusted OR = 0.67, 95% CI, 0.57-0.79). The rs9588884 GG displayed a lower level of miR-20a and the rs982873 CC displayed a lower level of miR-17. Additionally, the rare allele of rs9588884 G and the rs982873 C revealed a reduced luciferase activity. These findings indicate that the rs9588884 GG and the rs982873 CC in the promoter of miR-17-92 may protect against CRC, possibly by decreasing transcriptional activity and eventually resulting in lower levels of miR-20a and miR-17.