Neuroblastoma (NB) is TP53-wild type malignant childhood tumor. In addition to MDM2, many genetic and epigenetic regulators of p53 activity and its signaling pathway are known. Currently are not well known changes in p53 pathway its deregulation arising in NB. We have investigated changes of p53, MDM2 and miRNA miR-34 a/b/c, miR-137, miR-380-5p, miR-885-5p gene expression in NB and their impact in NB progression and survival.
We have analyzed tumor tissue samples of 61 patients with NB. MDM2 and p53 expression levels (EL) was detected with real-time PCR using TaqMan primers and microRNAs with TaqMan MicroRNA Assay, Applied Biosystems (USA). Results were normalized to relevant controls. FISH method was used for MYCN amplification (MNA) detection.
In this study we have found that higher MDM2 EL was associated with unfavorable clinical NB features (MNA (p<0.03), disease stage (p<0.001), indicating a link between MDM2 overexpression and the high-risk phenotype. MDM2 overexpression was associated with a significant decrease in event-free survival of NB patients (F-Cox criterion: 3.22, p < 0.001).
We have established that miR-34 a/b/c and miR-380-5p don’t have significant independent effect on the clinical behavior of NB, whereas low expression of miR-885-5p and miR-137 EL is associated with unfavorable disease course. Thus, low miR-885-5p and miR-137 EL in NB tumor cells correlated with MNA (p<0.05 and p<0.001), MDM2 overexpression (p<0.02 and p<0.001) and was significantly more common in patients with advanced NB stages (p<0.04). In addition, low miR-137 expression was associated with chemotherapy resistance (p<0.05). We have established significant decrease of event-free survival rates of patients with low miR-885-5p and miR-137 expression (F-Cox criterion: 3.54, p < 0.001 and F-Cox criterion: 2.89, p<0.02).
Deregulation of 53-mediated pathway due to alterations of its regulators genes and microRNAs expression is associated with an unfavorable outcome in NB. Alterations in aforementioned genes and microRNAs can be used as predictive and prognostic markers in NB.