Identification of RNA-Binding Proteins as Targetable Putative Oncogenes in Neuroblastoma

Abstract

Neuroblastoma is a common childhood cancer with almost a third of those affected still dying, thus new therapeutic strategies need to be explored. Current experimental therapies focus mostly on inhibiting oncogenic transcription factor signalling. Although LIN28B, DICER and other RNA-binding proteins (RBPs) have reported roles in neuroblastoma development and patient outcome, the role of RBPs in neuroblastoma is relatively unstudied. In order to elucidate novel RBPs involved in MYCN-amplified and other high-risk neuroblastoma subtypes, we performed differential mRNA expression analysis of RBPs in a large primary tumour cohort (n = 498). Additionally, we found via Kaplan–Meier scanning analysis that 685 of the 1483 tested RBPs have prognostic value in neuroblastoma. For the top putative oncogenic candidates, we analysed their expression in neuroblastoma cell lines, as well as summarised their characteristics and existence of chemical inhibitors. Moreover, to help explain their association with neuroblastoma subtypes, we reviewed candidate RBPs’ potential as biomarkers, and their mechanistic roles in neuronal and cancer contexts. We found several highly significant RBPs including RPL22L1, RNASEH2A, PTRH2, MRPL11 and AFF2, which remain uncharacterised in neuroblastoma. Although not all RBPs appear suitable for drug design, or carry prognostic significance, we show that several RBPs have strong rationale for inhibition and mechanistic studies, representing an alternative, but nonetheless promising therapeutic strategy in neuroblastoma treatment.

The MicroRNA Landscape of MYCN-Amplified Neuroblastoma

“…In this respect, the downregulation of ELAVL4 is consistent with its proposed role in promoting neural differentiation, as reviewed in (45). On the contrary, IGF2BP1 upregulation in MNA neuroblastoma is supported by previous studies in primary tumors, MYC/MYCN-driven transcriptional regulation and conserved oncofetal expression of the protein (13,14,46,47). Notably in this respect, the conserved upregulation or de novo synthesis of IGF2BP1 in cancer is primarily observed in progressed, de-differentiated malignancies, as demonstrated for instance in anaplastic thyroid carcinoma (48).…”

“…ELAVL4 was proposed to antagonize downregulation of MYCN expression by miR-17 (12). Expression of the oncofetal IGF2BP1 is upregulated in MNA neuroblastoma (13,14), promotes MYCN protein and RNA expression (13), and is considered a potent and conserved inhibitor of miRNA-dependent downregulation of oncogenic factors in cancer (15,16).…”

RNA-Binding Proteins as Regulators of Migration, Invasion and Metastasis in Oral Squamous Cell Carcinoma

“…We have summarized the classical as well as emerging hallmark functions of RBPs in Figure 1. Given their widespread impact on gene expression and signaling networks, mutations or defects in the expression or localization of RBPs can cause a broad range of diseases, e.g., neurodegeneration, obesity, hypertension, and cancer [55,[89][90][91][92][93][94][95][96]. In the next paragraph, we will highlight selected examples of RBPs that have been shown to contribute to the malignancy of oral cancer, especially its metastatic features.…”

Potential of Mitochondrial Ribosomal Genes as Cancer Biomarkers Demonstrated by Bioinformatics Results

“…MRPL11 is highly expressed in stage 4 neuroblastoma and is associated with a poor prognosis. Tigecycline, an FDA-approved broadspectrum antibiotic, may be an indirect therapeutic strategy for neuroblastoma via the dysregulation of MRPL11 (73,74).…”