Oncotarget

Research Papers:

A genome-wide microRNA profiling indicates miR-424-5p and miR-503-5p as regulators of ALK expression in neuroblastoma

Marilena De Mariano, Sara Stigliani, Stefano Moretti, Federica Parodi, Michela Croce, Cinzia Bernardi, Aldo Pagano, Gian Paolo Tonini, Silvano Ferrini and Luca Longo _

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Oncotarget. 2017; 8:56518-56532. https://doi.org/10.18632/oncotarget.17033

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Abstract

Marilena De Mariano1, Sara Stigliani2, Stefano Moretti3, Federica Parodi1, Michela Croce1, Cinzia Bernardi4, Aldo Pagano5,6, Gian Paolo Tonini7, Silvano Ferrini1 and Luca Longo1

1UOC Bioterapie, Dipartimento di Terapie Oncologiche Integrate, IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

2UOS Fisiopatologia della Riproduzione Umana, Dipartimento di Chirurgia Generale, Specialistica ed Oncologica, IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

3Université Paris-Dauphine, PSL Research University, CNRS, Department UMR [7243], LAMSADE, Paris, France

4Centre of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy

5Dipartimento di Terapie Oncologiche Integrate, IRCCS AOU San Martino-IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy

6Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy

7Neuroblastoma Laboratory, Pediatric Research Institute, Città della Speranza, Padua, Italy

Correspondence to:

Luca Longo, email: [email protected]

Keywords: neuroblastoma, microRNA, ALK, miR-424-5p, miR-503-5p

Received: October 04, 2016     Accepted: March 29, 2017     Published: April 11, 2017

ABSTRACT

The discovery of missense mutations of ALK gene identified this receptor tyrosine kinase as a therapeutic target in neuroblastoma (NB). Moreover, a high level of ALK protein has been associated with metastatic NB cases and with a worse prognosis, suggesting that also ALK overexpression is involved in NB tumorigenesis. Since miRNAs play key roles in the regulation of gene expression we aimed at identifying those miRNAs that can regulate ALK in NB. We therefore analyzed the genome-wide expression profile of miRNAs in two sample sets of 16 NB cell lines and 22 NB samples by using miRNA microarrays. Both sample sets were then divided into two subgroups showing high (ALK+) or low/absent (ALK-) expression of ALK. Results showed a down-regulation of 30 and 23 miRNAs (p-value <0.05) in the ALK+ group in NB cell lines and samples, respectively. Validation analysis indicated that miR-424-5p and miR-503-5p, belonging to the same cluster, were differentially expressed in both NB cell lines and tumor samples. Although only miR-424-5p showed a direct binding to ALK 3’-UTR, both miRNAs led to a remarkable decreasing of ALK protein as well as to the inhibition of cell viability in ALK+ NB cell lines. In conclusion, our data indicate that both miR-424-5p and miR-503-5p are involved in regulating ALK expression in NB, either by directly targeting ALK receptor or indirectly, and may thus serve as potential therapeutic tools in ALK dependent NBs.


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