The polymorphisms of miRNA‐binding site in MLH3 and ERCC1 were linked to the risk of colorectal cancer in a case–control study

Abstract

Colorectal cancer (CRC), as a malignant tumor of lower digestive tract, has been found to have an increasing morbidity and mortality in China. It was particularly important to find some earlier biomarkers to predict the risk and prognosis. In this study, several polymorphisms on 3′UTR of three DNA repair genes including MLH3 rs10862, ERCC1 rs3212986, ERCC1 rs735482, ERCC1 rs2336219, and OGG1 rs1052133 were chosen by bioinformatics exploration, and then, a case–control study of 200 CRC cases and controls was performed. Furthermore, a dual‐luciferase assay was also carried out to certify whether the candidate miRNA can regulate its target gene and the selected SNPs have a valid effect on the target miRNA. Finally, both of ERCC1 rs3212986 and MLH3 rs108621 were shown to be associated with the risk of CRC. Comparing with rs3212986 CC genotype, AA was at a higher risk (OR = 3.079, 95% CI: 1.192–7.952). For MLH3 rs108621, comparing with TT genotype, CC and TC were at a higher risk of CRC in male (OR = 5.171, 95% CI: 1.009–26.494; OR = 1.904, 95% CI: 1.049–3.455). Interestingly, an analysis combining both ERCC1 rs3212986 and MLH3 rs108621 also showed an increased risk of CRC. In addition, a dual‐luciferase assay showed that miR‐193a‐3p could regulate MLH3, and the polymorphism rs108621 could alter the miR‐193a‐3p binding to MLH3. Therefore, MLH3 rs108621 may be associated with the risk of CRC due to the effect of miR‐193a‐3p on MLH3, which reminded the possibility as potential susceptibility biomarkers to predict the risk of CRC.

Rs3212986 polymorphism, a possible biomarker to predict smoking‐related lung cancer, alters DNA repair capacity via regulating ERCC1 expression

“…As either oncogenes or tumor suppressors, miRNAs might have a synergistic effect of SNPs on individual DRC in relation to cancerous susceptibility . Since located in the ERCC1 3′UTR, rs3212986 was likely involved in post‐transcriptional regulation of ERCC1 by the specific binding of miRNAs as miR‐15a . Taken together the above results, although rs3213986 polymorphism mapping in overlapping genes ERCC1 and CD3EAP on chromosome 19 was involved in expression of two genes, the major effect of DRC was driven by regulating ERCC1 in 3′UTR, given the higher LD, unstable secondary structure, and posttranscriptional regulation of binding miRNAs.…”

“…ERCC1 (excision repair cross‐complementation group 1), OGG1 (8‐oxoguanine DNA glycosylase), and MLH3 (mutL homolog 3) are three key rate‐limiting enzymes involving in NER, BER, and MMR pathways, respectively. Single‐nucleotide polymorphisms (SNPs) in these genes are associated with the risk of cancers mainly due to the alerted DNA repair activity of respective enzymes . However, previous epidemiological investigation and genome‐wide association studies usually focus on the significance of polymorphisms in open reading frame (ORF), while the supporting data of “regulatory SNPs” on noncoding regions especially 3ʹUTR and its relation with lung cancer have been barely reported so far.…”

MicroRNA‐binding site polymorphisms and risk of colorectal cancer: A systematic review and meta‐analysis

“…According to the results based on five included studies, rs3212986 increased the risk of CRC in all genetic models, which was similar to previous meta‐analysis, we also found to the same results in East Asian population. This polymorphism is located in binding site of miR‐15a in 3'UTR of ERCC1 . The polymorphisms and mRNA level of this gene had previously been investigated in CRC …”

Potential of modern circulating cell-free DNA diagnostic tools for detection of specific tumour cells in clinical practice

“…High risk genes that can be used in the development of cancer diagnostics are APC, MLH1, MSH2, MSH6, POLE, TGFBR2, MLH3, POLD1, MUTYH, and AXIN2 ( 52 ). Mostly proteins act as tumour suppressors or are involved in DNA repair (Supplementary Table 3) ( 53 - 63 ).…”