Altered expression of miRNAs and methylation of their promoters are correlated in neuroblastoma
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Marco Maugeri1,*, Davide Barbagallo1,*, Cristina Barbagallo1,*, Barbara Banelli2,5,*, Stefania Di Mauro3, Francesco Purrello3, Gaetano Magro4, Marco Ragusa1,**, Cinzia Di Pietro1,**, Massimo Romani2,**, Michele Purrello1,**
1Dipartimento 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, EU
2UOS Epigenetica dei Tumori, IRCCS A.O.U. San Martino-IST, Genova, Italy, EU
3Dipartimento di Biomedicina Clinica e Molecolare, Università di Catania, Ospedale Garibaldi, Catania, Italy, EU
4Dipartimento di Scienze Mediche, Chirurgiche e Tecnologie Avanzate G.F. Ingrassia, Università di Catania, Catania, Italy, EU
5Department of HealthSciences, University of Genova, Genova, Italy, EU
*These authors have contributed equally to this work
**Senior Corresponding Authors
Michele Purrello, email: firstname.lastname@example.org
Keywords: miRNAs encoding genes, promoter methylation profiles, neuroblastoma, gene expression, 5’-AZA
Received: May 05, 2016 Accepted: October 21, 2016 Published: November 04, 2016
Neuroblastoma is the most common human extracranial solid tumor during infancy. Involvement of several miRNAs in its pathogenesis has been ascertained. Interestingly, most of their encoding genes reside in hypermethylated genomic regions: thus, their tumor suppressor function is normally disallowed in these tumors. To date, the therapeutic role of the demethylating agent 5’-Aza-2 deoxycytidine (5’-AZA) and its effects on miRNAome modulation in neuroblastoma have not been satisfactorily explored. Starting from a high-throughput expression profiling of 754 miRNAs and based on a proper selection, we focused on miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p as candidate miRNAs for our analysis. They resulted downregulated in four neuroblastoma cell lines with respect to normal adrenal gland. MiRNAs 29a-3p and 34b-3p also resulted downregulated in vivo in a murine neuroblastoma progression model. Unlike the amount of methylation of their encoding gene promoters, all these miRNAs were significantly overexpressed following treatment with 5’-AZA. Transfection with candidate miRNAs mimics significantly decreased neuroblastoma cells proliferation rate. A lower expression of miR-181c was significantly associated to a worse overall survival in a public dataset of 498 neuroblastoma samples (http://r2.amc.nl). Our data strongly suggest that CDK6, DNMT3A, DNMT3B are targets of miR-29a-3p, while CCNE2 and E2F3 are targets of miR-34b-3p. Based on all these data, we propose that miR-29a-3p, miR-34b-3p, miR-181c-5p and miR-517a-3p are disallowed tumor suppressor genes in neuroblastoma and suggest them as new therapeutic targets in neuroblastoma.
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