Abstract
BackgroundNeuroblastoma (NB) is one of the deadliest paediatric solid tumours due to its rapid proliferative characteristics. Amplified copies of MYCN are considered the most important marker for the prediction of tumour relapse and progression in NB, but they were only detected in 20–30% of NB patients, indicating there might be other oncogenes in the development of NB. The far upstream element binding protein 1 (FUBP1) was first identified as a transcriptional regulator of the proto-oncogene MYC. However, the expression and role of FUBP1 in NB have not been documented.MethodsFUBP1 expression was analysed from GEO database and verified by immunohistochemistry (IHC) and western blotting (WB) in NB tissues and cell lines. Cell proliferation and apoptosis were detected by Cell Counting Kit-8, Colony formation assay, EDU, TUNEL staining and flow cytometric analysis. Several glycolytic metabolites production was confirmed by ELISA and oxygen consuming rate (OCR). Luciferase assay, WB, chromatin immunoprecipitation (CHIP) were used to explore the mechanisms of the effect of FUBP1 on NB.ResultsFUBP1 mRNA levels were increased along with the increase in International Neuroblastoma Staging System (INSS) stages. High expression of FUBP1 with low N-Myc expression accounted for 44.6% of NB patient samples (n = 65). In addition, FUBP1 protein levels were remarkably increased with NB malignancy in the NB tissue microarray (NB: n = 65; ganglioneuroblastoma: n = 31; ganglioneuroma: n = 27). Furthermore, FUBP1 expression was negatively correlated with patient survival rate but positively correlated with ki67 content. In vitro experiments showed that FUBP1 promotes NB cell proliferation and inhibits cell apoptosis via enhancing glycolysis and ATP production. Mechanistically, FUBP1 inhibited the degradation of HIF1α via downregulation of Von Hippel-Lindau (VHL), the E3 ligase for HIF1α, resulting in upregulation of lactate dehydrogenase isoform B (LDHB) expression to enhance glycolysis. Overexpressed or silenced N-Myc could not regulate FUBP1 or LDHB levels.ConclusionsTaken together, our findings demonstrate for the first time that elevated FUBP1 promotes NB glycolysis and growth by targeting HIF1α rather than N-Myc, suggesting that FUBP1 is a novel and powerful oncogene in the development of NB independent of N-Myc and may have potential in the diagnosis and treatment of NB.
Highlights
Neuroblastoma (NB) is one of the deadliest paediatric solid tumours due to its rapid proliferative characteristics
far upstream element binding protein 1 (FUBP1) increased with the degree of NB malignancy and was negatively correlated with the survival rate independent of N-Myc To verify the key role of N-Myc, we analysed N-Myc expression in an NB Tissue Microarray (TMA, Additional file 1: Fig. S1B)
We found that the percentage of N-Myc high expression (H-Score ≥ 5; n = 24) in NB tissues (n = 65) was only 36.9%, while the percentage of N-Myc low expression (H-Score < 5; n = 41) in NB tissues (n = 65) was 63.1% (Fig. 1a and c)
Summary
Neuroblastoma (NB) is one of the deadliest paediatric solid tumours due to its rapid proliferative characteristics. Neuroblastoma (NB) originates from the nerve crest of the sympathetic nervous system and is one of the most common malignant extracranial solid tumours in children, accounting for approximately 10% of the malignant tumours in children and 15% of all paediatric cancer deaths [1]. Patients in very low-risk groups, such as partial M-S (INRG staging)/IV-S (INSS staging) patients, can self-resolve without any treatment [1, 2]. The progression-free survival rate of high-risk NB is low even with high-intensity comprehensive treatment, including chemotherapy, surgery, radiotherapy, autologous stem cell transplantation and immunotherapy [3]. There is no effective treatment for high-risk NB because the target of its pathogenesis is not clear
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