MYCNamplification (MNA) and disruption of tumor suppressor microRNA (TSmiR) function are key drivers of poor outcomes in neuroblastoma (NB). While MYCN and TSmiRs regulate glucose metabolism, their role in de novo fatty acid synthesis (FAS) and unsaturated FAS (UFAS) remains poorly understood. Here, we show that FAS and UFAS (U/FAS) genesFASN,ELOVL6,SCD,FADS2, andFADS1are upregulated in high-risk (HR) NB and that their expression is associated with lower overall survival. RNA-Seq analysis of human NB cell lines revealed parallel U/FAS gene expression patterns. Consistent with this, we found that NB-related TSmiRs were predicted to target these genes extensively. We further observed that both MYC and MYCN upregulated U/FAS pathway genes while suppressing TSmiR host gene expression, suggesting a possible U/FAS regulatory network between MYCN and TSmiRs in NB. NB cells are high in de novo synthesized omega 9 (ω9) unsaturated fatty acids and low in both ω6 and ω3, suggesting a means for NB to limit cell-autonomous immune stimulation and reactive oxygen species (ROS)-driven apoptosis from ω6 and ω3 unsaturated fatty acid derivatives, respectively. We propose a model in which MYCN and TSmiRs regulate U/FAS and play an important role in NB pathology, with implications for other MYC family-driven cancers.
MYCN扩增（MNA）与肿瘤抑制性微小RNA（TSmiR）功能破坏是导致神经母细胞瘤（NB）预后不良的关键驱动因素。虽然MYCN与TSmiR已知调控葡萄糖代谢，但它们在新发脂肪酸合成（FAS）及不饱和脂肪酸合成（UFAS）中的作用机制尚不明确。本研究发现，FAS与UFAS（合称U/FAS）通路关键基因FASN、ELOVL6、SCD、FADS2及FADS1在高危型NB中表达上调，且其表达水平与患者总生存率降低显著相关。通过对人类NB细胞系进行RNA测序分析，我们观察到U/FAS基因呈现协同表达模式。与此一致的是，生物信息学预测显示NB相关TSmiR可能广泛靶向调控这些基因。进一步研究发现，MYC与MYCN在抑制TSmiR宿主基因表达的同时，能上调U/FAS通路基因，提示MYCN与TSmiR可能在NB中构成U/FAS调控网络。NB细胞富含新合成的ω9不饱和脂肪酸，而ω6与ω3脂肪酸水平较低，这表明NB可能通过该代谢特征分别规避由ω6及ω3不饱和脂肪酸衍生物引发的细胞自主免疫刺激与活性氧（ROS）介导的细胞凋亡。本研究提出MYCN与TSmiR通过调控U/FAS通路在NB病理进程中发挥重要作用的模型，该机制也可能适用于其他MYC家族驱动的恶性肿瘤。
肿瘤(癌症)患者之家