The human rs1050286 polymorphism alters LOX-1 expression through modifying miR-24 binding.

Abstract

The up-regulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, plays a fundamental role in the pathogenesis of atherosclerosis. Moreover, OLR1 polymorphisms were associated with increased susceptibility to acute myocardial infarction (AMI) and coronary artery diseases (CAD). In these pathologies, the identification of therapeutic approaches that can inhibit or reduce LOX-1 overexpression is crucial. Predictive analysis showed a putative hsa-miR-24 binding site in the 3'UTR of OLR1, 'naturally' mutated by the presence of the rs1050286 single nucleotide polymorphism (SNP). Luciferase assays revealed that miR-24 targets OLR1 3'UTR-G, but not 3'UTR-A (P < 0.0005). The functional relevance of miR-24 in regulating the expression of OLR1 was established by overexpressing miR-24 in human cell lines heterozygous (A/G, HeLa) and homozygous (A/A, HepG2) for rs1050286 SNP. Accordingly, HeLa (A/G), but not HepG2 (A/A), showed a significant down-regulation of OLR1 both at RNA and protein level. Our results indicate that rs1050286 SNP significantly affects miR-24 binding affinity to the 3'UTR of OLR1, causing a more efficient post-transcriptional gene repression in the presence of the G allele. On this basis, we considered that OLR1 rs1050286 SNP may contribute to modify OLR1 susceptibility to AMI and CAD, so ORL1 SNPs screening could help to stratify patients risk.

• Authors: Elena Morini, Barbara Rizzacasa, Sabina Pucci, Chiara Polidoro, Fabrizio Ferrè, Daniela Caporossi, Manuela Helmer Citterich, Giuseppe Novelli, Francesca Amati
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 20 Issue 1 Pg. 181-7 (Jan 2016) ISSN: 1582-4934 [Electronic] England
• PMID: 26542080 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• 3' Untranslated Regions
• MIRN24 microRNA, human
• MicroRNAs
• OLR1 protein, human
• Scavenger Receptors, Class E

Topics

• 3' Untranslated Regions
• Base Sequence
• Binding Sites
• Coronary Artery Disease (genetics)
• Enzyme Repression
• Genetic Association Studies
• Genetic Predisposition to Disease
• HeLa Cells
• Hep G2 Cells
• Humans
• MicroRNAs (genetics, metabolism)
• Myocardial Infarction (genetics)
• Polymorphism, Single Nucleotide
• RNA Interference
• Scavenger Receptors, Class E (genetics, metabolism)
• Sequence Analysis, RNA