Pathway analysis of senescence-associated miRNA targets reveals common processes to different senescence induction mechanisms

Abstract

Multiple mechanisms of senescence induction exist including telomere attrition, oxidative stress, oncogene expression and DNA damage signalling. The regulation of the cellular changes required to respond to these stimuli and create the complex senescent cell phenotype has many different mechanisms. MiRNAs present one mechanism by which genes with diverse functions on multiple pathways can be simultaneously regulated. In this study we investigated 12 miRNAs previously identified as senescence regulators. Using pathway analysis of their target genes we tested the relevance of miRNA regulation in the induction of senescence. Our analysis highlighted the potential of these senescence-associated miRNAs (SA-miRNAs) to regulate the cell cycle, cytoskeletal remodelling and proliferation signalling logically required to create a senescent cell. The reanalysis of publicly available gene expression data from studies exploring different senescence stimuli also revealed their potential to regulate core senescence processes, regardless of stimuli. We also identified stimulus specific apoptosis survival pathways theoretically regulated by the SA-miRNAs. Furthermore the observation that miR-499 and miR-34c had the potential to regulate all 4 of the senescence induction types we studied highlights their future potential as novel drug targets for senescence induction.

Sequence Variation in Mature MicroRNA-499 Confers Unfavorable Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy

“…These functional experiments were convincingly verified by our previous findings that rs3746444C variants contributed an adverse role of prognosis in those patients with platinum-based chemotherapy. In addition, one study has reported that miR-499 had the potential to regulate the DNA damage signaling (48). Also, DNA repair-related genes and cisplatinum resistance genes, such as AKR1C3 (49,50), have higher expression in A549-miRNA-499-C cells than in A549-miRNA-499-T cells.…”

MiR-34 modulates Caenorhabditis elegans lifespan via repressing the autophagy gene atg9

“…Thus, our results suggest that miR-34 is not only a biomarker of aging, but also an effector of aging, which might be mediated through the inhibition of autophagy genes, at least partly, through Atg9. A number of studies have investigated the miR-34 family, particularly miR-34a, whose expression increases with age in mouse and model cells in microRNA microarray analyses (Lafferty-Whyte et al 2009). Recent studies have shown that miR-34 overexpression accelerates the aging process in aging human diploid cells (IMR90) (He et al 2007) and endothelial progenitor cells (EPCs) (Zhao et al 2010).…”

MiR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodelling

“…Several independent lines of evidence have indicated a critical role for miRs, as biomarkers of cellular senescence, in both replicative and stress-induced modulation of in vitro cellular senescence (Lafferty-Whyte et al 2009;Poliseno et al 2008;Wagner et al 2008;Li et al 2009Li et al , 2010Olivieri et al 2009). Human umbilical vein endothelial cells (HUVECs) have been extensively used as an in vitro endothelial model representing common functional and morphological features of the in vivo endothelial cells (Unterluggauer et al 2007).…”