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Genetic Variation rs7930 in the miR-4273-5p Target Site Is Associated With a Risk of Colorectal Cancer

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Genetic Variation rs7930 in the miR-4273-5p Target Site Is Associated With a Risk of Colorectal Cancer

Ah-Reum Lee et al. Onco Targets Ther.

Abstract

Purpose: MicroRNAs (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 methods: SNPs 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.

Results: Individuals 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.

Conclusion: rs7930 is an independent genetic risk factor for CRC susceptibility. Our study suggests a mechanism of how this SNP contributes to CRC carcinogenesis.

Keywords: SNP; colorectal cancer; frequency; miR-4273-5p; rs7930; susceptibility.

Conflict of interest statement

The authors report no conflicts of interests in this work.

Figures

Figure 1
Figure 1
A decrease in the expression of the TOMM20 A allele construct relative to that of the G allele construct by miR-4273-5p demonstrated by a luciferase assay. Notes: (A) Schema of miR-4273-5p selection based on interaction prediction using two website-based software programs. (B) Relative renilla luciferase activity normalized against firefly luciferase activity. Each CRC cell line (SW620, SNUC4, DLD1, and HCT116) was transfected with the control mimic or miR-4273-5p mimic and then each of the reporter constructs with the G or A allele of rs7930 in the TOMM20 3′ UTR. A statistically significant decrease in expression was seen with psiCHECK/h_TOMM20_3′ UTR_A allele in all cell lines. Abbreviations: TOMM20, translocate of outer mitochondria membrane; UTR, untranslation region; CRC, colorectal cancer.
Figure 2
Figure 2
TOMM20 protein expression levels in CRC cell lines. Note: Quantifications of Western blot analysis of TOMM20 expression relative to β-actin in CRC cells. Abbreviations: CRC, colorectal cancer; TOMM20, translocate of outer mitochondria membrane.
Figure 3
Figure 3
SNP rs7930 variations in the TOMM20 3′ UTR affects TOMM20 expression via interaction with miR-4273-5p. Notes: (A) Regulation of the TOMM20 protein expression level according to the rs7930 genotype by miR-4273-5p in CRC cell lines. (B) The level of the TOMM20 protein was reversed by a miR-4273-5p inhibitor. Abbreviations: SNP, single-nucleotide polymorphism; TOMM20, translocate of outer mitochondria membrane; CRC, colorectal cancer; UTR, untranslation region.

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