Tan Kezhe, Wu Wei, Zhu Kai, Lu Li, Lv Zhibao
Department of General Surgery, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
J Cancer. 2022 Mar 28;13(7):2105-2125. doi: 10.7150/jca.69408. eCollection 2022.
Neuroblastoma (NB) is a pediatric cancer occurring in the peripheral nervous system. A demethylase, alkylation repair homolog protein 5 (ALKBH5), is one type of N6-methyladenosine (m6A) eraser that plays a tumor-suppressive role in a variety of cancers. The significance of carbohydrate metabolism in cancer has been intensively investigated over the years, but the correlation between ALKBH5 and glucose metabolism in NB remains to be elucidated. Based on the overlapped genes (DE-GRGs) of ALKBH5-related differentially expressed genes (ALKBH5-DEGs) in GSE62564 (n=498) and genes related to glucose metabolism (GRGs), a LASSO regression model was constructed. External validations with datasets (EGAS00001001308, n=139 & GSE16476, n=88) and the NB samples from Shanghai Children's Hospital (SCH) were performed. Meanwhile, biological and clinical utility, immune cell subtypes and drug sensitivity were assessed. ALKBH5 was significantly correlated with better overall survival (OS) in NB patients, and gene set enrichment analysis (GSEA) showed its enrichment in GO/ KEGG terms regarding glucose metabolism. 27 of the 31 DE-GRGs were included in the LASSO screen after the univariate analysis. A prognostic glucometabolic model including AHCY, NCAN, FBP2, GALNT3 and AKR1C2 was established with the internal and external validation with biological experiments: the high-risk subtype compared to the low-risk subtype showed oncogenic and MYCN-related malignancy, glucometabolic dysregulation, poor prognosis and immunosuppression. TGX-221 was predicted to be a potential therapeutic drug and validated to suppress NB oncogenes including MYCN, AHCY and NCAN and immunosuppressive DNMT1 in NB cells. ALKBH5 was closely related to glucometabolic processes, and our prognostic model had high application value in predicting & assessing the OS of NB patients, and even served potential drug targets.
神经母细胞瘤（NB）是一种发生于外周神经系统的儿科癌症。去甲基化酶——烷基化修复同源蛋白5（ALKBH5）是N6-甲基腺苷（m6A）去甲基酶的一种，在多种癌症中发挥肿瘤抑制作用。多年来，碳水化合物代谢在癌症中的意义已得到深入研究，但NB中ALKBH5与葡萄糖代谢之间的相关性仍有待阐明。基于GSE62564（n = 498）中ALKBH5相关差异表达基因（ALKBH5-DEGs）的重叠基因（DE-GRGs）以及与葡萄糖代谢相关的基因（GRGs），构建了LASSO回归模型。使用数据集（EGAS00001001308，n = 139和GSE16476，n = 88）以及来自上海儿童医学中心（SCH）的NB样本进行外部验证。同时，评估了生物学和临床效用、免疫细胞亚型及药物敏感性。ALKBH5与NB患者更好的总生存期（OS）显著相关，基因集富集分析（GSEA）显示其在与葡萄糖代谢相关的GO/KEGG术语中富集。单因素分析后，31个DE-GRGs中的27个被纳入LASSO筛选。通过内部和外部生物学实验验证，建立了一个包括AHCY、NCAN、FBP2、GALNT3和AKR1C2的预后糖代谢模型：与低风险亚型相比，高风险亚型表现出致癌性和与MYCN相关的恶性肿瘤、糖代谢失调、预后不良和免疫抑制。预测TGX-221为一种潜在治疗药物，并验证其可抑制NB细胞中的包括MYCN、AHCY和NCAN在内的NB致癌基因以及免疫抑制性DNMT1。ALKBH5与糖代谢过程密切相关，我们的预后模型在预测和评估NB患者的OS方面具有很高的应用价值，甚至可作为潜在的药物靶点。
