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Genetic variant in miR-21 binding sites is associated with colorectal cancer risk.

ABSTRACT: Single nucleotide polymorphisms (SNPs) within binding sites of microRNAs (miRNAs) could modify cancer susceptibility by changing the binding affinity of miRNAs on their target mRNA 3'-untranslated regions (UTRs). MicroRNA-21 (miR-21) is involved in the development of colorectal cancer. However, the relationship between SNPs within the binding sites of miR-21 and colorectal cancer risk has not been widely investigated. A case-control study including 1147 patients and 1203 controls was performed to evaluate the association of SNPs in miR-21 binding sites and colorectal cancer risk. Dual-luciferase reporter assays and functional assays were performed to evaluate the effects of miR-21. The SNP rs6504593 C allele conferred an increased risk of colorectal cancer compared with the T allele in an additive model (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36, P = 0.011). Dual-luciferase reporter assays demonstrated that the rs6504593 T allele negatively post-transcriptionally regulated IGF2BP1 by altering the binding affinity of miR-21. Additionally, colorectal cancer cells transiently transfected with miR-21 mimics promoted cell proliferation and suppressed apoptosis, whereas inhibition of miR-21 decreased cell growth. These data suggest that the miR-21 binding site SNP rs6504593 in the IGF2BP1 3'-UTR may alter IGF2BP1 expression and contribute to colorectal cancer risk.

SUBMITTER: Xie L

PROVIDER: S-EPMC6378227 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Genetic variant in miR-21 binding sites is associated with colorectal cancer risk.

Xie Lisheng L Li Shuwei S Jin Jing J He Lei L Xu Kaili K Zhu Lingjun L Du Mulong M Liu Yanqing Y Chu Haiyan H Zhang Zhengdong Z Wang Meilin M Shi Danni D Gu Dongying D Ni Min M

Journal of cellular and molecular medicine 20181219 3

Single nucleotide polymorphisms (SNPs) within binding sites of microRNAs (miRNAs) could modify cancer susceptibility by changing the binding affinity of miRNAs on their target mRNA 3'-untranslated regions (UTRs). MicroRNA-21 (miR-21) is involved in the development of colorectal cancer. However, the relationship between SNPs within the binding sites of miR-21 and colorectal cancer risk has not been widely investigated. A case-control study including 1147 patients and 1203 controls was performed t ...[more]

PMID: 30569605

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Project description:BackgroundSingle nucleotide polymorphisms (SNPs) located in microRNA (miRNA) binding sites can affect the interactions between miRNAs and target genes, which is related to cancer susceptibility and tumorigenesis. However, the association between SNPs located in miR-17-92 cluster binding sites and ESCC risk remains unclear. Therefore, we aimed to explore the relationship between polymorphisms in miR-17-92 cluster binding sites and ESCC susceptibility.MethodsSix SNPs in the binding sites of miR-17-92 cluster were selected using bioinformatics databases, and their association with ESCC risk was investigated in a case-control study (including 488 cases and 512 controls) based on the population from high incidence areas of ESCC in China. We evaluated the SNP-SNP and SNP-smoking interactions using generalized multifactor dimensionality reduction (GMDR). Moreover, the expression of the miR-17-92 cluster and its target genes was determined in ESCC and adjacent normal tissues by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was conducted to verify the effect of SNPs on the binding affinity between miRNAs and target genes.ResultsWe found that the SNP rs1804506 C > T had a significant association with the decreased ESCC risk. The SNP rs1804506 T allele was associated with a significantly decreased risk of ESCC in the additive model (OR = 0.817, 95% CI = 0.681-0.981, P = 0.030). The rs1804506 T allele had more striking effects on reducing ESCC risk in older individuals, female or non-smoker subgroups. We also found a significant interaction effect between rs1366600 and smoking by GMDR methods (P = 0.011). Additionally, the expression levels of miR-19a-3p and TGFBR3 were significantly downregulated in ESCC tissues compared with normal tissues, and the carriers of rs1804506 TT genotype had lower expression level of TGFBR3 than those of rs1804506 CC/CT genotype. Following dual-luciferase reporter assay showed that the rs1804506 T allele reduced the binding of miR-19a-3p and TGFBR3 3'-UTR.ConclusionsOur findings suggest that the rs1804506 polymorphism in miR-17-92 cluster binding sites contributes to the susceptibility of ESCC, which might provide new clues and scientific evidence for the etiology and biomarkers for the prevention and treatment of ESCC.

Dataset Information

Genetic variant in miR-21 binding sites is associated with colorectal cancer risk.

Publications

Genetic variant in miR-21 binding sites is associated with colorectal cancer risk.

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