• Jinwen Chen, Yali Xu, Ping Wu, Xinghe Chen, Wuwei Weng, and Dumiao Li.
• Department of Pediatric Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, P.R. China.
• World Neurosurg. 2022 Aug 1; 164: e99-e112.

ObjectiveNeuroblastoma is one of the most common extracranial solid tumors in children. The forkhead transcription factor FOXO3a has been implicated in the progression of a variety of human diseases. Here, we aim to identify the effects of FOXO3a on the malignancy of neuroblastoma.MethodsBioinformatics analysis was employed to identify differentially expressed genes related to neuroblastoma and the downstream regulator of FOXO3a. FOXO3a expression was examined in SH-SY5Y neuroblastoma cells. Interactions between FOXO3a and microRNA-21 (miR-21) were then identified using bioinformatics analysis and dual-luciferase reporter assay. After ectopic expression and depletion experiments in SH-SY5Y cells, cell malignant phenotypes were assessed by cell counting kit-8 and Transwell assays. FOXO3a-overexpressing neuroblastoma cells were xenografted into nude mice to validate the role of FOXO3a in tumor growth.ResultsDownregulated expression of FOXO3a was observed in neuroblastoma cells, with a negative correlation between FOXO3a and miR-21 expression. FOXO3a bound to the promoter region of miR-21 to downregulate its expression, resulting in inhibition of SH-SY5Y cell malignant phenotypes. Additionally, miR-21 targeted SPRY2 by binding to the 3'UTR of the mRNA encoding SPRY2, activating the extracellular signal-regulated kinase (ERK) pathway. FOXO3a disrupted the binding of miR-21 to SPRY2 and inactivated ERK to suppress the malignant phenotypes of SH-SY5Y cells as well as tumor growth in vivo.ConclusionsIn conclusion, FOXO3a may inhibit the progression of neuroblastoma by suppressing the miR-21 expression and facilitating SPRY2-dependent ERK pathway inactivation.Copyright © 2022 Elsevier Inc. All rights reserved.

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