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Single nucleotide polymorphisms in microRNA binding sites on the HOX genes regulate carcinogenesis: An in-silico approach.

ABSTRACT: Homeobox proteins, encoded by HOX genes, are transcriptional factors playing a crucial role in the master regulatory pathway in the cells. Any mutations in HOX genes will affect the expression of its allied proteins. Such mutations were correlated to the development of different cancer types. In this study, we found 15 HOX genes with a potential target to miRNA, which regulates the translation of the protein by binding to its mRNA through the 3'UTR region. Single nucleotide polymorphisms (SNPs) in this binding region could drastically affect the protein expression by affecting the number and the stability of miRNA-mRNA complexes. We found 77 miRNAs in 15 genes which were found to have altered binding efficiency because of 26 SNPs. After which, we tried to evaluate the impact of each of these SNPs on related HOX genes. Some SNPs such as SNP 15689 on the HOXB7 gene will decrease gene expression by creating or enhancing new binding sites for miRNA to mRNA, while other SNPs such as SNP 872760 on the HOXB5 gene will overexpress the gene by breaking or decreasing existing binding sites from miRNA to mRNA. Then we conducted an expression analysis to compare the mRNA expression profiles in normal and cancer tissue. Subsequently, we did an enrichment analysis followed by a network analysis to shed light on the metabolic function of the gene that could be affected by mutation and whether these mutations may affect other genes. For the first time, this study delivers information on the possible epigenetic regulation of HOX genes via the 77 miRNAs that have predicted target binding sites on HOX mRNAs, and SNPs may regulate those. Furthermore, we show that the HOX gene misregulation may influence other HOX and non-HOX genes, based on network analysis.

SUBMITTER: El-Huneidi W

PROVIDER: S-EPMC8326182 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: MicroRNA dysregulation is a common event in leukemia. Polymorphisms in microRNA-binding sites (miRSNPs) in target genes may alter the strength of microRNA interaction with target transcripts thereby affecting protein levels. In this study we aimed at identifying miRSNPs associated with leukemia risk and assessing impact of these miRSNPs on miRNA binding to target transcripts. METHODS: We analyzed with specialized algorithms the 3' untranslated regions of 137 leukemia-associated genes and identified 111 putative miRSNPs, of which 10 were chosen for further investigation. We genotyped patients with acute myeloid leukemia (AML, n?=?87), chronic myeloid leukemia (CML, n?=?140), childhood acute lymphoblastic leukemia (ALL, n?=?101) and healthy controls (n?=?471). Association between SNPs and leukemia risk was calculated by estimating odds ratios in the multivariate logistic regression analysis. For miRSNPs that were associated with leukemia risk we performed luciferase reporter assays to examine whether they influence miRNA binding. RESULTS: Here we show that variant alleles of TLX1_rs2742038 and ETV6_rs1573613 were associated with increased risk of childhood ALL (OR (95% CI)?=?3.97 (1.43-11.02) and 1.9 (1.16-3.11), respectively), while PML_rs9479 was associated with decreased ALL risk (OR?=?0.55 (0.36-0.86). In adult myeloid leukemias we found significant associations between the variant allele of PML_rs9479 and decreased AML risk (OR?=?0.61 (0.38-0.97), and between variant alleles of IRF8_ rs10514611 and ARHGAP26_rs187729 and increased CML risk (OR?=?2.4 (1.12-5.15) and 1.63 (1.07-2.47), respectively). Moreover, we observed a significant trend for an increasing ALL and CML risk with the growing number of risk genotypes with OR?=?13.91 (4.38-44.11) for carriers of ?3 risk genotypes in ALL and OR?=?4.9 (1.27-18.85) for carriers of 2 risk genotypes in CML. Luciferase reporter assays revealed that the C allele of ARHGAP26_rs187729 creates an illegitimate binding site for miR-18a-3p, while the A allele of PML_rs9479 enhances binding of miR-510-5p and the C allele of ETV6_rs1573613 weakens binding of miR-34c-5p and miR-449b-5p. CONCLUSIONS: Our study implicates that microRNA-binding site polymorphisms modulate leukemia risk by interfering with the miRNA-mediated regulation. Our findings underscore the significance of variability in 3' untranslated regions in leukemia.

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Single nucleotide polymorphisms in microRNA binding sites on the HOX genes regulate carcinogenesis: An in-silico approach.

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