title: Comparative analysis of gene expression data reveals novel targets of senescence-associated microRNAs.
abstract: In the last decades, cellular senescence is viewed as a complex mechanism involved in different processes, ranging from tumor suppression to induction of age-related degenerative alterations. Senescence-inducing stimuli are myriad and, recently, we and others have demonstrated the role exerted by microRNAs in the induction and maintenance of senescence, by the identification of a subset of Senescence-Associated microRNAs (SAmiRs) up-regulated during replicative or stress-induced senescence and able to induce a premature senescent phenotype when over-expressed in human primary cells. With the intent to find novel direct targets of two specific SAmiRs, SAmiR-494 and -486-5p, and cellular pathways which they are involved in, we performed a comparative analysis of gene expression profiles available in literature to select genes down-regulated upon replicative senescence of human primary fibroblasts. Among them, we searched for SAmiR's candidate targets by analyzing with different target prediction algorithms their 3'UTR for the presence of SAmiR-binding sites. The expression profiles of selected candidates have been validated on replicative and stress-induced senescence and the targeting of the 3'UTRs was assessed by luciferase assay. Results allowed us to identify Cell Division Cycle Associated 2 (CDCA2) and Inhibitor of DNA binding/differentiation type 4 (ID4) as novel targets of SAmiR-494 and SAmiR-486-5p, respectively. Furthermore, we demonstrated that the over-expression of CDCA2 in human primary fibroblasts was able to partially counteract etoposide-induced senescence by mitigating the activation of DNA Damage Response.
authors.affiliation: IRCCS SDN Foundation, Naples, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Napolitano
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy; CEINGE - Advanced Biotechnologies, Naples, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Comegna
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy; CEINGE - Advanced Biotechnologies, Naples, Italy.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Succoio
authors.affiliation: CEINGE - Advanced Biotechnologies, Naples, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Leggiero
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy; CEINGE - Advanced Biotechnologies, Naples, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Pastore
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy; CEINGE - Advanced Biotechnologies, Naples, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Faraonio
authors.affiliation: IRCCS SDN Foundation, Naples, Italy; Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy; CEINGE - Advanced Biotechnologies, Naples, Italy.
authors.forename: Filiberto
authors.initials: F
authors.lastname: Cimino
authors.affiliation: Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy; CEINGE - Advanced Biotechnologies, Naples, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Passaro
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D016922:Cellular Senescence / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics
chemical_list: C509224:CDCA2 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins