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, Luca Longo

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)56518-56532
Number of pages15
JournalOncotarget
Volume8
Issue number34
DOIs
Publication statusPublished - 2017

Keywords

  • ALK
  • MicroRNA
  • MiR-424-5p
  • MiR-503-5p
  • Neuroblastoma

ASJC Scopus subject areas

  • Oncology

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    De Mariano, M., Stigliani, S., Moretti, S., Parodi, F., Croce, M., Bernardi, C., Pagano, A., Tonini, G. P., Ferrini, S., & Longo, L. (2017). A genome-wide microRNA profiling indicates miR-424-5p and miR-503-5p as regulators of ALK expression in neuroblastoma. Oncotarget, 8(34), 56518-56532. https://doi.org/10.18632/oncotarget.17033