Abstract 3103: IGF2BP1 and MYCN cooperate in an oncogenic feedback loop, in high-risk neuroblastoma

Abstract

Abstract Previous studies have shown chromosomal 17q21-ter amplification in neuroblastoma is both a common and highly prognostic 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 essential for neurocrest migration during development. This study analyzes for the first time the DNA copy number and expression of the IGF2BP1 gene in neuroblastoma, and importantly dissects the previously unknown molecular interplay of the IGF2BP1 and MYCN oncogenes. Firstly, IGF2BP1 was found to be highly expressed in neuroblastoma and outperformed other described oncogenes, including MYCN, by Kaplan-meier analyses of mRNA microarray data sets. High IGF2BP1 mRNA expression was significantly associated with stage 4 tumors (P = 0.019), and decreased patient survival (P = 6.3e-05). IGF2BP1 was also associated with MYCN amplification and MYCN mRNA expression. Additionally, in another patient cohort we found DNA copy number, mRNA and protein levels were all significantly higher in stage 4 disease as compared with localised disease. Significantly, high IGF2BP1 protein expression was associated with lower patient survival (p = 0.0249). IGF2BP1 protein expression was significantly correlated with MYCN mRNA levels. In vitro studies, confirmed IGF2BP1's promotion of MYCN, as IGF2BP1 knockdown decreased MYCN RNA and protein expression. Interestingly, IGF2BP1 is an RNA-binding protein, and is known to target MYC, PTEN, IGF-2, MDR1, and other transcripts important in neuroblastoma. We determined that IGF2BP1 decreased MYCN RNA half-life. Moreover, we have evidence showing MYCN promotes IGF2BP1 expression, including that the MYCN protein binds the IGF2BP1 promoter and also that IGF2BP1 is significantly upregulated in precancer cells, in a MYCN-driven neuroblastoma mouse model. Finally, ongoing work aims to determine miRNAs significantly reduced in stage 4 tumors neuroblastoma versus lower-risk stages. We have performed and analysed Next Generation miRNA Sequencing from 30 neuroblastoma tumors, the most extensive study of its type in neuroblastoma to date. We have elucidated several novel miRNAs with great prognostic and drugable-target potential in neuroblastoma, as well as a putative role in regulating the IGF2BP1-MYCN signaling loop. These data demonstrate, for the first-time, IGF2BP1 as a potential oncogene and biomarker in neuroblastoma, which has an important role within MYCN-driven carcinogenesis. Citation Format: Jessica L. Bell, Turlapati Raseswari, Tao Liu, Bernard Atmadibrata, Daniel Carter, Glenn Marshall, Knut Krohn, Stefan Hüttelmaier. IGF2BP1 and MYCN cooperate in an oncogenic feedback loop, in high-risk neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3103. doi:10.1158/1538-7445.AM2014-3103