Abstract
Neuroblastoma (NB) arises from the embryonic neural crest and is the most common extracranial solid tumor in children under 5 years of age. Reduced expression of Dicer1 has recently been shown to be in correlation with poor prognosis in NB patients. This study aimed to investigate the mechanisms that could lead to the down-regulation of Dicer1 in neuroblastoma. We used computational prediction to identify potential miRs down-regulating Dicer1 in neuroblastoma. One of the miRs that were predicted to target Dicer1 was miR-192. We measured the levels of miR-192 in 43 primary tumors using real time PCR. Following the silencing of miR-192, the levels of dicer1 cell viability, cell proliferation and migration capability were analyzed. Multivariate analysis identified miR-192 as an independent prognostic marker for relapse in neuroblastoma patients (p=0.04). We were able to show through a dual luciferase assay and side-directed mutational analysis that miR-192 directly binds the 3' UTR of Dicer1 on positions 1232-1238 and 2282-2288. An increase in cell viability, proliferation and migration rates were evident in NB cells transfected with miR-192-mimic. Yet, there was a significant decrease in proliferation when NB cells were transfected with an miR-192-inhibitor We suggest that miR-192 might be a key player in NB by regulating Dicer1 expression.
Highlights
Neuroblastoma (NB) arises from the embryonic neural crest and is the most common extracranial solid tumor in children under 5 years of age [1]
We identified a significant correlation between Progression free survival (PFS) and Dicer1 expression at 10 years: patients with high Dicer1 expression levels had 87% PFS versus 59% in patients with low Dicer1 expression (p=0.032, Figure 2)
Since Dicer1 is located on 14q32.13, we evaluated the deletion of chromosome 14q32 by Multiplex Ligation-dependent Probe Amplification (MLPA)
Summary
Neuroblastoma (NB) arises from the embryonic neural crest and is the most common extracranial solid tumor in children under 5 years of age [1]. The clinical heterogeneity of NB has been reported to be associated with a variety of biological and molecular features: aged 18 months or more, advanced stages 3 and 4, adrenal primary site, MYCN amplification (MYCNA) and diploid or tetraploid DNA index (DI) are considered adverse indicators [1]. MicroRNAs (miRs) are non-coding, single-stranded 18-24 nucleotide RNA molecules that base-pair with target mRNAs and negatively regulate their stability and translation efficiency [2,3]. More than 50% of miRs are located in cancer-associated genomic regions or in fragile sites, suggesting that miRs play an important role in pathogenesis of human cancers [4]. Dicer together with Drosha, catalyze the sequential cleavage of miR maturation [5]
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