Cheng Jian, Sun Miaomiao, Dong Xiao, Yang Yang, Qin Xiaohan, Zhou Xing, Fu Yongcheng, Wang Yuanyuan, Wang Jingyue, Zhang Da
Department of Pediatric Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Pediatrics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
BMC Cancer. 2025 Jan 28;25(1):161. doi: 10.1186/s12885-025-13560-y.
Neuroblastoma, a prevalent extracranial solid tumor in pediatric patients, demonstrates significant clinical heterogeneity, ranging from spontaneous regression to aggressive metastatic disease. Despite advances in treatment, high-risk neuroblastoma remains associated with poor survival. SLC1A5, a key glutamine transporter, plays a dual role in promoting tumor growth and immune modulation. However, its contributions to neuroblastoma biology remain largely unexplored.
This study utilized clinical neuroblastoma samples from 20 patients and 1310 cases from four public datasets to investigate SLC1A5 expression, biological function, and prognostic significance. Differential expression, Kaplan-Meier survival analysis, gene set enrichment analysis, and weighted correlation network analysis were conducted. Functional validation included qPCR, immunohistochemistry, Western blotting, and cell proliferation assays using the SLC1A5 inhibitor V-9302. A prognostic signature, SRPS, was constructed and validated using machine-learning approaches. Immune infiltration analysis was performed to evaluate the tumor immune microenvironment.
SLC1A5 expression was significantly elevated in high-risk neuroblastoma and correlated with advanced stages and poor prognosis. GSEA revealed mTORC1 signaling enrichment in high SLC1A5 expression groups, validated by increased p-p70S6K levels in tumor samples and neuroblastoma cells. V-9302 treatment suppressed mTORC1 signaling and inhibited cell proliferation. Hub-genes were identified to form the SRPS model, which demonstrated superior prognostic performance compared to existing models. Immune infiltration analysis revealed a more immunosuppressive tumor microenvironment associated with high SLC1A5 expression. Additionally, SLC1A5 negatively regulated ST8SIA1, a gene crucial for GD2 biosynthesis, suggesting that SLC1A5 inhibition may enhance GD2-directed immunotherapies.
SLC1A5 plays a pivotal role in neuroblastoma by promoting tumor progression and shaping an immunosuppressive microenvironment. The SRPS model, incorporating SLC1A5-associated genes, offers robust prognostic utility. Targeting SLC1A5 through advanced drug delivery systems and combined metabolic-immunotherapeutic strategies may enhance treatment specificity and efficacy. These findings provide a foundation for novel therapeutic approaches to improve outcomes in high-risk neuroblastoma patients.
神经母细胞瘤是儿科患者中常见的颅外实体瘤，具有显著的临床异质性，范围从自发消退到侵袭性转移性疾病。尽管治疗取得了进展，但高危神经母细胞瘤的生存率仍然很低。SLC1A5是一种关键的谷氨酰胺转运蛋白，在促进肿瘤生长和免疫调节中起双重作用。然而，其对神经母细胞瘤生物学的贡献在很大程度上仍未被探索。
本研究利用20例患者的临床神经母细胞瘤样本和来自四个公共数据集的1310例样本，研究SLC1A5的表达、生物学功能和预后意义。进行了差异表达分析、Kaplan-Meier生存分析、基因集富集分析和加权相关网络分析。功能验证包括qPCR、免疫组织化学、蛋白质印迹以及使用SLC1A5抑制剂V-9302进行细胞增殖试验。使用机器学习方法构建并验证了一个预后特征SRPS。进行免疫浸润分析以评估肿瘤免疫微环境。
SLC1A5在高危神经母细胞瘤中的表达显著升高，且与晚期和不良预后相关。基因集富集分析显示，在SLC1A5高表达组中mTORC1信号通路富集，肿瘤样本和神经母细胞瘤细胞中p-p70S6K水平升高证实了这一点。V-9302处理抑制了mTORC1信号通路并抑制了细胞增殖。鉴定出枢纽基因以形成SRPS模型，该模型与现有模型相比具有更好的预后性能。免疫浸润分析显示，与SLC1A5高表达相关的肿瘤微环境具有更强的免疫抑制作用。此外，SLC1A5负向调节ST8SIA1，这是一种对GD2生物合成至关重要的基因，表明抑制SLC1A5可能增强针对GD2的免疫疗法。
SLC1A5通过促进肿瘤进展和塑造免疫抑制微环境在神经母细胞瘤中起关键作用。包含与SLC1A5相关基因的SRPS模型具有强大的预后效用。通过先进的药物递送系统靶向SLC1A5以及联合代谢免疫治疗策略可能会提高治疗的特异性和疗效。这些发现为改善高危神经母细胞瘤患者预后的新型治疗方法提供了基础。
