The role of microRNAs in neuroblastoma cell differentiation and their therapeutic potential: a systematic review

Neuroblastoma (NB) is the most common extracranial solid tumor in children under five years of age. NB tumors can arise anywhere along the sympathetic chain due to the failure of neural crest cells to appropriately migrate and differentiate. Despite aggressive multimodal therapies, high-risk NB has persistently low survival rates due to genetic heterogeneity, aggressive tumor biology, and disease relapse that is exceedingly difficult to treat. One strategy for treating NB tumors is to promote their differentiation into a more benign histologic phenotype. Retinoic acid (RA) is a vitamin A derivative that decreases cell proliferation and promotes NB cell differentiation to a more mature phenotype. RA is commonly utilized in the maintenance phase of treatment to reduce the risk of NB recurrence, but unfortunately, rates of relapse remain high. MicroRNAs (miRs) are small noncoding RNAs that regulate post-transcriptional gene expression and may promote differentiation effects in NB cells thereby representing novel therapeutics. This systematic review highlights miRs with known roles in differentiation of NB cells by discussing their major targets and pathways as well as their potential role in treatment for NB patients. Consistent with PRISMA 2020 recommendations, a systematic literature search was performed in Ovid MEDLINE and Embase databases from inception to June 2023. Articles were selected for inclusion based on relevance to the role of miRs in differentiation and NB; articles not focused on miRs, differentiation, or NB, and non-English publications were excluded. A total of 396 articles from this search underwent abstract and full-text screening to yield 89 articles matching our selection criteria. Our review revealed 53 entries comprising individual miRNAs and miRNA groups with a role in the differentiation of NB. miR-124, miR-34, and miR-506-3p are well studied with significant stimulation of NB differentiation. Disruption of these miRs is correlated with decreased overall survival in patients. The miR-17–92 cluster was found to antagonize NB differentiation and is associated with poor survival. Preclinical evidence suggests that miR-124, miR-34, and miR-506-3p families may promote differentiation of NB cells toward a more mature phenotype, though substantial translational barriers remain before clinical application. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD42023476550 , identifier CRD42023476550.