PurposeMicroRNAs (miRNAs) are noncoding RNAs that play roles as tumor suppressors or oncogenes by regulating the expression of target genes via binding to seed-match sequences. Polymorphisms in the miRNA-binding site of a target gene can alter miRNA binding and potentially affect the risk of cancer. The objective of this study was to identify single-nucleotide polymorphisms (SNPs) in miRNA-binding sites and assess their involvement in the risk of colorectal cancer (CRC).Materials and methodsSNPs in the 3′ untranslated regions of genes were selected and assessed for their effects on CRC risk in Korean population using participants in Korean Cancer Prevention Study-II. A detailed study was carried out with the SNP rs7930 in the 3′ untranslated region of the translocase of outer mitochondrial membrane 20 (TOMM20) gene. A case–control study (1,545 controls and 620 CRC cases) was conducted to analyze the relationship between polymorphism at rs7930 and the risk of CRC. An interacting miRNA was predicted using web-based software programs, and its interaction with rs7930 in CRC cell lines was investigated by using a luciferase assay.ResultsIndividuals carrying the rs7930 AG genotype (G allele) had a 1.721-fold increased risk for CRC in comparison with those with the AA genotype (A allele). The miRNA miR-4273-5p was found to specifically interact with the A allele of rs7930 and to suppress the expression of the target gene (TOMM20) in CRC cell lines.Conclusionrs7930 is an independent genetic risk factor for CRC susceptibility. Our study suggests a mechanism of how this SNP contributes to CRC carcinogenesis.

Colorectal cancer (CRC) is one of the most common cancers and has a high rate of morbidity and mortality worldwide. Very-low-density-lipoprotein receptor (VLDLR), a member of the low-density-lipoprotein receptor (LDLR) superfamily, is a multifunctional receptor that regulates cellular signaling by binding numerous ligands. Several studies reported the altered expression of VLDLR and suggested that VLDLR may play a critical role in tumor development by affecting cell proliferation and metastasis. However, the function of VLDLR and regulation of its expression by miRNAs have not been investigated in CRC. In the present study, we investigated the expression of VLDLR in CRC patients and found it to be significantly decreased in tumors in comparison with paired adjacent non-tumor tissues. Moreover, VLDLR over-expression inhibited the proliferation and migration of CRC cells. We also found that VLDLR expression was negatively regulated by miR-200c in CRC cells and that their expression levels were inversely correlated in CRC patients. These data suggest that VLDLR down-regulation mediated by the increased expression of miR-200c may be involved in the development of CRC.

MicroRNA (miRNA) are a class of single‐stranded, small non‐coding RNA that regulate various biological processes, including skin and hair cycle regulation, by modulating the expression of specific genes at the post‐transcriptional level. Recently, several studies reported that miRNA directly or indirectly up‐regulate target genes. Previously, we performed microarray analysis to identify the target genes of miR‐199a‐5p in a mouse skin keratinocyte cell line and detected more than 200 genes whose expression was significantly increased by miR‐199a‐5p overexpression (> 1.5‐fold). In this study, we further investigated these genes and found that cyclin B1 (Ccnb1) expression was positively regulated by miR‐199a‐5p in keratinocyte. Moreover, Ccnb1 expression was inversely correlated with miR‐199a‐5p expression during the mouse hair cycle. Cell cycle analysis showed that the proportion of cells in S phase was slightly increased, while the proportion of cells in G2/M phase decreased by miR‐199‐5p. Using luciferase assay, we found that the 3′ untranslated region of Ccnb1 was a direct target of miR‐199a‐5p. We also found that the regulation of Ccnb1 expression by miR‐199a‐5p is mouse specific. CCNB1 expression was not affected in the human and monkey cell lines. These results provide a new relationship between Ccnb1 and miR‐199a‐5p in both mouse keratinocyte and miRNA biology.