title: Epigenetic dysregulation in neuroblastoma: A tale of miRNAs and DNA methylation.
abstract: In neuroblastoma, the epigenetic landscape is more profoundly altered in aggressive compared to lower grade tumors and the concomitant hypermethylation of many genes, defined as "methylator phenotype", has been associated with poor outcome. DNA methylation can interfere with gene expression acting at distance through the methylation or demethylation of the regulatory regions of miRNAs. The multiplicity of miRNA targets may result in the simultaneous alteration of many biological pathways like cell proliferation, apoptosis, migration and differentiation. We have analyzed the methylation status of a set of miRNAs in a panel of neuroblastoma cell lines and identified a subset of hypermethylated and down-regulated miRNAs (miRNA 34b-3p, miRNA 34b-5p, miRNA34c-5p, and miRNA 124-2-3p) involved in the regulation of cell cycle, apoptosis and in the control of MYCN expression. These miRNAs share, in part, some of the targets whose expression is inversely correlated to the methylation and expression of the corresponding miRNA. To simulate the effect of the demethylation of miRNAs, we transfected the corresponding miRNA-mimics in the same cell lines and observed the down-regulation of a set of their target genes as well as the partial block of the cell cycle and the activation of the apoptotic pathway. The epigenetic alterations of miRNAs described in the present study were found also in a subset of patients at high risk of progression. Our data disclosed a complex network of interactions between epigenetically altered miRNAs and target genes, that could interfere at multiple levels in the control of cell homeostasis.
authors.affiliation: Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST, Genova, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Parodi
authors.affiliation: Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST, Genova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Carosio
authors.affiliation: Dipartimento di Scienze Biomediche e Biotecnologiche, Sezione di Biologia e Genetica G Sichel, Unità di BioMedicina Molecolare, Genomica e dei Sistemi Complessi, Università di Catania, Catania, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ragusa
authors.affiliation: Dipartimento di Scienze Biomediche e Biotecnologiche, Sezione di Biologia e Genetica G Sichel, Unità di BioMedicina Molecolare, Genomica e dei Sistemi Complessi, Università di Catania, Catania, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Di Pietro
authors.affiliation: Dipartimento di Scienze Biomediche e Biotecnologiche, Sezione di Biologia e Genetica G Sichel, Unità di BioMedicina Molecolare, Genomica e dei Sistemi Complessi, Università di Catania, Catania, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Maugeri
authors.affiliation: Dipartimento di Scienze Biomediche e Biotecnologiche, Sezione di Biologia e Genetica G Sichel, Unità di BioMedicina Molecolare, Genomica e dei Sistemi Complessi, Università di Catania, Catania, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Barbagallo
authors.affiliation: University of Bari, DETO, Bari, Italy and C.A.R.S.O. Consortium, Valenzano, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Sallustio
authors.affiliation: Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST, Genova, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Allemanni
authors.affiliation: Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST, Genova, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Pistillo
authors.affiliation: Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST, Genova, Italy.
authors.forename: Ida
authors.initials: I
authors.lastname: Casciano
authors.affiliation: Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST, Genova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Forlani
authors.affiliation: University of Bari, DETO, Bari, Italy and C.A.R.S.O. Consortium, Valenzano, Italy.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Schena
authors.affiliation: Dipartimento di Scienze Biomediche e Biotecnologiche, Sezione di Biologia e Genetica G Sichel, Unità di BioMedicina Molecolare, Genomica e dei Sistemi Complessi, Università di Catania, Catania, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Purrello
authors.affiliation: Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST, Genova, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Romani
authors.affiliation: Laboratory of Tumor Epigenetics, IRCCS AOU San Martino - IST, Genova, Italy; Department of Health Sciences, University of Genova, Italy. Electronic address: banellib.epigenetics@gmail.com.
authors.forename: Barbara
authors.initials: B
authors.lastname: Banelli
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000145:classification / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D016019:Survival Analysis
chemical_list: D035683:MicroRNAs
keywords: DNA methylation; Epigenetic network; Neuroblastoma; miRNA