title: EPO Mediates Neurotrophic, Neuroprotective, Anti-Oxidant, and Anti-Apoptotic Effects via Downregulation of miR-451 and miR-885-5p in SH-SY5Y Neuron-Like Cells.
abstract: Erythropoietin (EPO) is a neuroprotective cytokine, which has been applied in several animal models presenting neurological disorders. One of the proposed modes of action resulting in neuroprotection is post-transcriptional gene expression regulation. This directly brings to mind microRNAs (miRNAs), which are small non-coding RNAs that regulate gene expression at the post-transcriptional level. It has not yet been evaluated whether miRNAs participate in the biological effects of EPO or whether it, inversely, modulates specific miRNAs in neuronal cells. In this study, we employed miRNA and mRNA arrays to identify how EPO exerts its biological function. Notably, miR-451 and miR-885-5p are downregulated in EPO-treated SH-SY5Y neuronal-like cells. Accordingly, target prediction and transcriptome analysis of cells treated with EPO revealed an alteration of the expression of genes involved in apoptosis, cell survival, proliferation, and migration. Low expression of miRNAs in SH-SY5Y was correlated with high expression of their target genes, vascular endothelial growth factor A, matrix metallo peptidase 9 (MMP9), cyclin-dependent kinase 2 (CDK2), erythropoietin receptor, Mini chromosome maintenance complex 5 (MCM5), B-cell lymphoma 2 (BCL2), and Galanin (GAL). Cell viability, apoptosis, proliferation, and migration assays were carried out for functional analysis after transfection with miRNA mimics, which inhibited some biological actions of EPO such as neuroprotection, anti-oxidation, anti-apoptosis, and migratory effects. In this study, we report for the first time that EPO downregulates the expression of miRNAs (miR-451 and miR-885-5p) in SH-SY5Y neuronal-like cells. The correlation between the over-expression of miRNAs and the decrease in EPO-mediated biological effects suggests that miR-451 and miR-885-5p may play a key role in the mediation of biological function.
authors.affiliation: Advanced Biomedical Research Center, Dokuz Eylul University , Izmir , Turkey ; Department of Neuroscience, Health Science Institute, Dokuz Eylul University , Izmir , Turkey.
authors.forename: Begum
authors.initials: B
authors.lastname: Alural
authors.affiliation: Department of Neuroscience, Health Science Institute, Dokuz Eylul University , Izmir , Turkey.
authors.forename: Gizem Ayna
authors.initials: GA
authors.lastname: Duran
authors.affiliation: Advanced Biomedical Research Center, Dokuz Eylul University , Izmir , Turkey ; Department of Neuroscience, Health Science Institute, Dokuz Eylul University , Izmir , Turkey.
authors.forename: Kemal Ugur
authors.initials: KU
authors.lastname: Tufekci
authors.affiliation: Department of Molecular Biology and Genetics, Izmir Institute of Technology , Urla , Turkey.
authors.forename: Jens
authors.initials: J
authors.lastname: Allmer
authors.affiliation: Department of Neuroscience, Health Science Institute, Dokuz Eylul University , Izmir , Turkey.
authors.forename: Zeynep
authors.initials: Z
authors.lastname: Onkal
authors.affiliation: Department of Neuroscience, Health Science Institute, Dokuz Eylul University , Izmir , Turkey.
authors.forename: Dogan
authors.initials: D
authors.lastname: Tunali
authors.affiliation: Department of Neuroscience, Health Science Institute, Dokuz Eylul University , Izmir , Turkey.
authors.forename: Kursad
authors.initials: K
authors.lastname: Genc
authors.affiliation: Advanced Biomedical Research Center, Dokuz Eylul University , Izmir , Turkey ; Department of Neuroscience, Health Science Institute, Dokuz Eylul University , Izmir , Turkey.
authors.forename: Sermin
authors.initials: S
authors.lastname: Genc
keywords: apoptosis; cell death; erythropoietin; miRNAs; migration; neurite outgrowth; oxidative stress; proliferation