Musashi-2 (MSI2) promotes neuroblastoma tumorigenesis through targeting MYC-mediated glucose-6-phosphate dehydrogenase (G6PD) transcriptional activation

Neuroblastoma (NB) is the deadliest pediatric solid tumor due to its rapid proliferation. Aberrant expression of MYCN is deemed as the most remarkable feature for the predictive hallmark of NB progression and recurrence. However, the phenomenon that only detection of MYCN in the nearly 20% of NB patients hints that there should be other vital oncogenes in the progression of NB. Here, we firstly show that MSI2 mRNA is augmented by analyzing public GEO datasets in the malignant stage according to International Neuroblastoma Staging System (INSS) stages. Although accumulating evidences uncover the emerging roles of MSI2 in several cancers, the regulatory functions and underlying mechanisms of MSI2 in NB remain under-investigated. Herein, we identified that high-expressed MSI2 and low-expressed n-Myc group account for 43.1% of total NB clinical samples (n = 65). Meanwhile, MSI2 expression is profoundly upregulated along with NB malignancy and negatively associated with the survival outcome of NB patients in the NB tissue microarray (NB: n = 65; Ganglioneuroblastoma: n = 31; Ganglioneuroma: n = 27). In vitro, our results revealed that MSI2 promoted migration, invasion, and proliferation of NB cells via enhancing pentose phosphate pathway. Mechanistically, MSI2 upregulated the key enzyme glucose-6-phosphate dehydrogenase (G6PD) via directly binding to 3'-untranslated regions of c-Myc mRNA to facilitate its stability, resulting in enhancing pentose phosphate pathway. Our findings reveal that MSI2 promotes pentose phosphate pathway via activating c-Myc-G6PD signaling, suggesting that MSI2 exhibits a novel and powerful target for the diagnosis and treatment of NB.