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.
Highlights
Neuroblastoma (NB) is a neural crest-derived pediatric cancer that shows a peculiar heterogeneity in its clinical presentation and outcome as well as in the molecular mechanisms that underlie its genetic predisposition and aggressiveness [1, 2]
To identify miRNAs differentially expressed between Anaplastic Lymphoma Kinase (ALK)+ and ALK- NB cell lines we carried out analyses in a set of NB cell lines to determine both mRNA and protein ALK expression
Since ALK turned up as a key oncogene involved in the tumorigenesis of at least a subset of NB patients, great efforts have been made to develop an efficient system for its targeting, mainly by taking advantage of small molecule inhibitors, such as crizotinib
Summary
Neuroblastoma (NB) is a neural crest-derived pediatric cancer that shows a peculiar heterogeneity in its clinical presentation and outcome as well as in the molecular mechanisms that underlie its genetic predisposition and aggressiveness [1, 2]. ALK catalytic domain was originally identified in the t(2;5)(p23;q35) chromosomal translocation that produces the oncogenic fusion of the amino terminus of nucleophosmin (NPM) to the catalytic intracellular domain of ALK [7]. This rearrangement occurs in most of the Anaplastic Large Cell Lymphomas (ALCL), which mainly affect children and young adults [7]. ALK has been found to be involved in several other cancers, mainly as a consequence of different chromosomal translocations such as those reported in inflammatory myofibroblastic tumors [8], non-small cell lung cancer [9] and diffuse large B-cell lymphomas [10]. Crizotinib showed limited activity in NB patients with ALK-activating mutations [20] that revealed differential sensitivity to ALK inhibitors in both preclinical and clinical studies [18, 21]
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