Regulation of Neuroblastoma Cell Differentiation by Retinoic Acid: Role of Alternative Splicing and micro-RNAs

High-risk metastatic neuroblastoma tumors have a poor prognosis even after aggressive multimodal therapeutic protocols. Retinoic Acid (RA) treatments were included in these multimodal therapies because its ability to induce differentiation of neuroblastoma cells in vitro and it appears to reduce the risk of tumor recurrence as established in a large multicentre clinical assay. The present article deals with the molecular actions of RA on neuroblastoma cells. We want to discuss novel actions of RA at the post-transcriptional level (alternative splicing, translational control of specific mRNAs, microRNA regulation) that in addition to the well-characterized actions of RA at the transcriptional level contribute to neuroblastoma cell differentiation. We propose that RA acts coordinately over the multiple regulatory layers of gene expression and therefore must be considered as a global regulator of gene expression in neuroblastoma cells.