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SNP Regulation of microRNA Expression and Subsequent Colon Cancer Risk.

ABSTRACT: INTRODUCTION:MicroRNAs (miRNAs) regulate messenger RNAs (mRNAs) and as such have been implicated in a variety of diseases, including cancer. MiRNAs regulate mRNAs through binding of the miRNA 5' seed sequence (~7-8 nucleotides) to the mRNA 3' UTRs; polymorphisms in these regions have the potential to alter miRNA-mRNA target associations. SNPs in miRNA genes as well as miRNA-target genes have been proposed to influence cancer risk through altered miRNA expression levels. METHODS:MiRNA-SNPs and miRNA-target gene-SNPs were identified through the literature. We used SNPs from Genome-Wide Association Study (GWAS) data that were matched to individuals with miRNA expression data generated from an Agilent platform for colon tumor and non-tumor paired tissues. These samples were used to evaluate 327 miRNA-SNP pairs for associations between SNPs and miRNA expression levels as well as for SNP associations with colon cancer. RESULTS:Twenty-two miRNAs expressed in non-tumor tissue were significantly different by genotype and 21 SNPs were associated with altered tumor/non-tumor differential miRNA expression across genotypes. Two miRNAs were associated with SNP genotype for both non-tumor and tumor/non-tumor differential expression. Of the 41 miRNAs significantly associated with SNPs all but seven were significantly differentially expressed in colon tumor tissue. Two of the 41 SNPs significantly associated with miRNA expression levels were associated with colon cancer risk: rs8176318 (BRCA1), ORAA 1.31 95% CI 1.01, 1.78, and rs8905 (PRKAR1A), ORGG 2.31 95% CI 1.11, 4.77. CONCLUSION:Of the 327 SNPs identified in the literature as being important because of their potential regulation of miRNA expression levels, 12.5% had statistically significantly associations with miRNA expression. However, only two of these SNPs were significantly associated with colon cancer.

SUBMITTER: Mullany LE

PROVIDER: S-EPMC4667940 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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SNP Regulation of microRNA Expression and Subsequent Colon Cancer Risk.

Mullany Lila E LE Wolff Roger K RK Herrick Jennifer S JS Buas Matthew F MF Slattery Martha L ML

PloS one 20151202 12

<h4>Introduction</h4>MicroRNAs (miRNAs) regulate messenger RNAs (mRNAs) and as such have been implicated in a variety of diseases, including cancer. MiRNAs regulate mRNAs through binding of the miRNA 5' seed sequence (~7-8 nucleotides) to the mRNA 3' UTRs; polymorphisms in these regions have the potential to alter miRNA-mRNA target associations. SNPs in miRNA genes as well as miRNA-target genes have been proposed to influence cancer risk through altered miRNA expression levels.<h4>Methods</h4>Mi ...[more]

PMID: 26630397

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Project description:MicroRNAs (miRNAs) have been implicated in the incidence and progression of cancer. It has been proposed that single nucleotide polymorphisms (SNPs) influence cancer risk due to their position within genes involved in miRNA synthesis and regulation.Genes directly and indirectly involved in miRNA biogenesis were identified from the literature. We then identified SNPs within these regions. Using genome-wide association study data we evaluated associations between biogenesis-related SNPs with colon cancer risk and their corresponding mRNA expression in normal colonic mucosa and carcinoma and difference in expression between the two tissues. SNPs that were associated with either altered colon cancer risk or with mRNA expression were evaluated for associations with altered miRNA expression.Eleven SNPs were associated (P?<?0.05) with colon cancer risk, and two of these variants remained significant after correction for multiple comparisons (PHolm?<?0.05): rs1967327 (PRKRA) (ORdom?=?0.78, 95 % CI 0.66-0.92) and rs4548444 (MAPKAP2) (ORrec?=?1.67, 95 % CI 1.12-2.48). Of these two SNPs, rs4548444 (MAPKAP2), was associated with significantly altered miRNA expression levels in normal colonic mucosa, with nine miRNAs upregulated among individuals homozygous rare (GG) for rs4548444. One SNP associated with cancer prior to adjustment for multiple comparisons, rs11089328 (DGCR8), was associated with altered levels of hsa-miR-645 in differential tissue under the dominant model. Three SNPs, rs2740349 (GEMIN4) in carcinoma tissue, and rs235768 (BMP2) and rs2059691 (PRKRA) in normal mucosa, were significantly associated with altered mRNA expression levels across genotypes after multiple comparison adjustment. Rs2740349 (GEMIN4) and rs235768 (BMP2) were significantly associated with the upregulation of six and nine individual miRNAs in normal colonic mucosa, respectively.Our data suggest that few of the SNPs in biogenesis genes we evaluated alter levels of mRNA transcription or colon cancer risk. As only one SNP both alters colon cancer risk and miRNA expression it is likely that SNPs influencing cancer do not do so through miRNAs. Because the significant SNPs were associated with downregulated mRNAs and upregulated miRNAs, and because each SNP was associated with unique miRNAs, it is possible that other mechanisms influence mature miRNA levels.

Project description:Two mature miRNA species may be generated from the 5' and 3' arms of a pre-miRNA precursor. In most cases, only one species remains while the complementary species is degraded. However, co-existence of miRNA-5p and -3p species is increasingly being reported. In this work, we aimed to systematically investigate co-expression of miRNA-5p/3p in colon cancer cells in a genome-wide analysis, and to examine cross-targeting of the dysregulated miRNAs and 5p/3p species.Four colon cancer cell lines were examined relative to two normal colon tissues. Of the 1,190 miRNAs analyzed, 92 and 36 were found to be up- or down-regulated, respectively, in cancer cells. Nineteen co-expressed miRNA-5p/3p pairs were further identified suggesting frequent 5p/3p co-accumulation in colon cancer cells. Of these, 14 pairs were co-up-regulated and 3 pairs were co-down-regulated indicating concerted 5p/3p dysregulation. Nine dysregulated miRNA pairs fell into three miRNA gene families, namely let-7, mir-8/200 and mir-17, which showed frequent cross-targeting in the metastasis process. Focusing on the let-7d-5p/3p pair, the respectively targeted IGF1R and KRAS were shown to be in a reverse relationship with expression of the respective miRNA, which was confirmed in transient transfection assays using let-7d mimic or inhibitor. Targeting of KRAS by let-7d was previous reported; targeting of IGF1R by let-7d-5p was confirmed in luciferase assays in this study. The findings of let-7d-5p/3p and multiple other miRNAs targeting IGF1R, KRAS and other metastasis-related factors suggest that 5p/3p miRNAs contribute to cross-targeting of multiple cancer-associated factors and processes possibly to evade functional abolishment when any one of the crucial factors are inactivated.miRNA-5p/3p species are frequently co-expressed and are coordinately regulated in colon cancer cells. In cancer cells, multiple cross-targeting by the miRNAs, including the co-existing 5p/3p species, frequently occurs in an apparent safe-proof scheme of miRNA regulation of important tumorigenesis processes. Further systematic analysis of co-existing miRNA-5p/3p pairs in clinical tissues is important in elucidating 5p/3p contributions to cancer pathogenesis.

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SNP Regulation of microRNA Expression and Subsequent Colon Cancer Risk.

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SNP Regulation of microRNA Expression and Subsequent Colon Cancer Risk.

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