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.

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

De Mariano, Marilena;Bernardi, Cinzia;Pagano, Aldo;Ferrini, Silvano;
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.
File in questo prodotto:
File Dimensione Formato  
demariano et al.pdf

accesso aperto

Descrizione: pdf pubblicazione
Tipologia: Documento in versione editoriale
Dimensione 3.75 MB
Formato Adobe PDF
3.75 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11567/888107
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 17
  • ???jsp.display-item.citation.isi??? 14
social impact