Previous studies have shown chromosomal 17q21-ter amplification in neuroblastoma is both a common and prognostically significant event. The oncogene, insulin-like growth factor-2 mRNA-binding protein-1 (IGF2BP1), is located near the proximal edge of this amplified region. IGF2BP1 is also required for neurocrest migration during development. This study analyzes IGF2BP1's importance in neuroblastoma both in vivo and in vitro.
mRNA expression levels of IGF2BP genes were determined and 68 of 88 tumours (75 %) expressed substantial IGF2BP1 mRNA (by microarray). High IGF2BP1 mRNA expression was significantly associated with stage 4 tumours (P = 0.019), and decreased patient survival (P = 6.3e-05). Another patient tumour cohort was analysed for IGF2BP1 DNA, mRNA and protein levels. Increased IGF2BP1 DNA copy numbers were found in over 80 % of tumours. IGF2BP1 DNA copy number, mRNA and protein was significantly higher is stage 4 disease as compared with localised disease. Significantly, high IGF2BP1 protein expression was associated with lower patient survival (p = 0.0249). Finally, IGF2BP1 protein expression was significantly correlated with MYCN mRNA levels.
When compared to other known neuroblastoma markers, such as MYCN, ALK and LIN28B, IGF2BP1 differentiates survival of individuals better than or equal to these reported markers.
In vitro studies, showed IGF2BP1 knock down via siRNAs decreases MYCN RNA and protein expression. This knockdown also had a phenotypic effect on the neuroblastoma cells, including decreased cell viability. As IGF2BP1 is an RNA-binding protein, and is known to target MYC, PTEN, IGF-2, and other transcripts relevant to neuroblastoma, ongoing work will determine if IGF2BP1’s RNA binding function is a crucial factor, and if the microRNAs suppressing IGF2BP1 are lacking in neuroblastoma (via RNA deep sequencing of 30 neuroblastoma tumours). Importantly, the miRNAome dataset will be used to find novel miRNAs important in neuroblastoma, independent of IGF2BP1 targeting. It's one of the most comprehensive miRNA deep sequencing efforts of neuroblastoma to date.
These data demonstrate, for the first-time, IGF2BP1 as a potential oncogene and neuroblastoma biomarker.