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A polymorphism at the miR-502 binding site in the 3' untranslated region of the SET8 gene is associated with the outcome of small-cell lung cancer.

ABSTRACT: microRNAs (miRNAs) bind to the 3' untranslated regions (UTRs) of messenger RNAs, where they interfere with translation of genes that regulate cell differentiation, apoptosis and tumourigenesis. The histone methyltransferase SET8 has been reported to methylate TP53 and regulate genomic stability. We analysed a single nucleotide polymorphism (rs16917496) within the miR-502 miRNA seed region at the 3' UTR of SET8 in small-cell lung cancer (SCLC) patients. The SET8 CC+CT genotype was identified to be independently associated with longer survival in SCLC patients by multivariate analysis (relative risk, 0.453; 95% CI 0.217-0.944; p=0.035). The analysis of genetic polymorphisms in miRNA binding sites may help to identify patient subgroups at high risk of poor outcome.

SUBMITTER: Ding C

PROVIDER: S-EPMC3438626 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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A polymorphism at the miR-502 binding site in the 3' untranslated region of the SET8 gene is associated with the outcome of small-cell lung cancer.

Ding Cuimin C Li Ruijuan R Peng Jingcui J Li Shengmian S Guo Zhanjun Z

Experimental and therapeutic medicine 20120203 4

microRNAs (miRNAs) bind to the 3' untranslated regions (UTRs) of messenger RNAs, where they interfere with translation of genes that regulate cell differentiation, apoptosis and tumourigenesis. The histone methyltransferase SET8 has been reported to methylate TP53 and regulate genomic stability. We analysed a single nucleotide polymorphism (rs16917496) within the miR-502 miRNA seed region at the 3' UTR of SET8 in small-cell lung cancer (SCLC) patients. The SET8 CC+CT genotype was identified to b ...[more]

PMID: 22969952

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Project description:The transcription factor AP-2α functions as a tumor suppressor by regulating various genes that are involved in cell proliferation and apoptosis. Chemotherapeutic drugs including cisplatin induce post-transcriptionally endogenous AP-2α, which contributes to chemosensitivity by enhancing therapy-induced apoptosis. microRNAs (miRNAs) miR-200b, miR-200c and miR-429 (miR-200b/200c/429) are up-regulated in endometrial and esophageal cancers, and their overexpression correlates with resistance to cisplatin treatment. Using computational programs, we predicted that the 3' untranslated region (UTR) of AP-2α gene contains a potential miRNA response element (MRE) for the miR-200b/200c/429 family, and the single nucleotide polymorphism (SNP) site rs1045385 (A or C allele) resided within the predicted MRE. Luciferase assays and Western blot analysis demonstrated that the miR-200b/200c/429 family recognized the MRE in the 3' UTR of AP-2α gene and negatively regulated the expression of endogenous AP-2α proteins. SNP rs1045385 A>C variation enhanced AP-2α expression by disrupting the binding of the miR-200b/200c/429 family to the 3' UTR of AP-2α. The effects of the two polymorphic variants on cisplatin sensitivity were determined by clonogenic assay. The overexpression of AP-2α with mutant 3' UTR (C allele) in the endometrial cancer cell line HEC-1A, which has high levels of endogenous miR-200b/200c/429 and low levels of AP-2α protein, significantly increased cisplatin sensitivity, but overexpression of A allele of AP-2α has no significant effects, compared with mock transfection. We concluded that miR-200b/200c/429 induced cisplatin resistance by repressing AP-2α expression in endometrial cancer cells. The SNP (rs1045385) A>C variation decreased the binding of miR-200b/200c/429 to the 3' UTR of AP-2α, which upregulated AP-2α protein expression and increased cisplatin sensitivity. Our results suggest that SNP (rs1045385) may be a potential prognostic marker for cisplatin treatment.

Project description:Osteonectin/SPARC is one of the most abundant noncollagenous extracellular matrix proteins in bone, regulating collagen fiber assembly and promoting osteoblast differentiation. Osteonectin-null and haploinsufficient mice have low-turnover osteopenia, indicating that osteonectin contributes to normal bone formation. In male idiopathic osteoporosis patients, osteonectin 3' untranslated region (UTR) single-nucleotide polymorphism (SNP) haplotypes that differed only at SNP1599 (rs1054204) were previously associated with bone mass. Haplotype A (containing SNP1599G) was more frequent in severely affected patients, whereas haplotype B (containing SNP1599C) was more frequent in less affected patients and healthy controls. We hypothesized that SNP1599 contributes to variability in bone mass by modulating osteonectin levels. Osteonectin 3' UTR reporter constructs demonstrated that haplotype A has a repressive effect on gene expression compared with B. We found that SNP1599G contributed to an miR-433 binding site, and miR-433 inhibitor relieved repression of the haplotype A, but not B, 3' UTR reporter construct. We tested our hypothesis in vivo, using a knock-in approach to replace the mouse osteonectin 3' UTR with human haplotype A or B 3' UTR. Compared with haplotype A mice, bone osteonectin levels were higher in haplotype B mice. B mice displayed higher bone formation rate and gained more trabecular bone with age. When parathyroid hormone was administered intermittently, haplotype B mice gained more cortical bone area than A mice. Cultured marrow stromal cells from B mice deposited more mineralized matrix and had higher osteocalcin mRNA compared with A mice, demonstrating a cell-autonomous effect on differentiation. Altogether, SNP1599 differentially regulates osteonectin expression and contributes to variability in bone mass, by a mechanism that may involve differential targeting by miR-433. This work validates the findings of the previous candidate gene study, and it assigns a physiological function to a common osteonectin allele, providing support for its role in the complex trait of skeletal phenotype. © 2014 American Society for Bone and Mineral Research.

Dataset Information

A polymorphism at the miR-502 binding site in the 3' untranslated region of the SET8 gene is associated with the outcome of small-cell lung cancer.

Publications

A polymorphism at the miR-502 binding site in the 3' untranslated region of the SET8 gene is associated with the outcome of small-cell lung cancer.

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