Liu Luqian, Zhang Fengyu, Yu Jiaye, Dong Pingping, Deng Jing, Liu Weiwei, Cao Xinlei, Huang Juanjuan, Lin Xiaoming, Xue Xiangyang
Wenzhou Collaborative Innovation Center of Gastrointestinal Cancer in Basic Research and Precision Medicine, Wenzhou Key Laboratory of Cancer-related Pathogens and Immunity, Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
School of Biomedical Engineering, Tianjin Medical University, Tianjin, China.
Front Immunol. 2025 Jun 5;16:1603898. doi: 10.3389/fimmu.2025.1603898. eCollection 2025.
Researchers are currently concentrating on molecular markers and potential therapeutic targets associated with gastric cancer in light of recent developments in precision medicine and molecular biology. Disulfidptosis was first proposed in 2023 as a novel programmed cell death mode associated with the cytoskeleton. Disulfidptosis-related proteins are essential for the preservation of protein stability and abnormal expression of disulfidptosis-related genes may be linked to cancer development and drug resistance.
The gastric cancer transcriptomic data were retrieved from TCGA database, and disulfidptosis-related genes were identified through literature search. Utilizing machine learning methods such as LASSO, Random Forest (RF), Boruta, SVM-RFE, and XGBoost, the disulfidptosis-related gene NUBPL was determined as a potential predictor for gastric cancer. PPI network was constructed, and the GO database as well as the KEGG database were employed to analyze the protein interactions and pathway enrichment of NUBPL in gastric cancer. Meanwhile, the ESTIMATE algorithm was used for immune infiltration analysis and prediction of immunotherapy response, and the Genomics of Drug Sensitivity in Cancer (GDSC) database was utilized for the drug sensitivity analysis of NUBPL. The role of NUBPL in gastric cancer and its inhibition of disulfidptosis were validated using molecular biological methods.
The aberrant expression of NUBPL significantly impacts the prognosis of gastric cancer and modulates metabolic and immune-related pathways. In patients with elevated NUBPL expression levels, a reduced number of CD8-positive T cells is associated with adverse prognosis and gastric cancer progression. Elevated NUBPL expression levels can impair the function of chemokines. Moreover, patients with lower NUBPL expression levels exhibit better responses to immunotherapy. We have also identified drugs such as QS11, Imatinib, and AS601245 as potential inhibitors of NUBPL. experiments have shown that NUBPL affects the invasion and migration of gastric cancer cells, rather than proliferation and apoptosis, by regulating the PPP pathway and inhibiting disulfidptosis.
This study underscores the pivotal role of NUBPL in gastric cancer progression and highlights its significance as a potential target for targeted therapy and immunotherapy gastric cancer, NUBPL, disulfidptosis, biomarker, immunotherapy, machine learning.
鉴于精准医学和分子生物学的最新进展，研究人员目前正专注于与胃癌相关的分子标志物和潜在治疗靶点。二硫键介导的细胞焦亡于2023年首次被提出，是一种与细胞骨架相关的新型程序性细胞死亡模式。二硫键介导的细胞焦亡相关蛋白对于维持蛋白质稳定性至关重要，二硫键介导的细胞焦亡相关基因的异常表达可能与癌症发展和耐药性有关。
从TCGA数据库中检索胃癌转录组数据，并通过文献检索确定二硫键介导的细胞焦亡相关基因。利用LASSO、随机森林（RF）、Boruta、支持向量机递归特征消除（SVM-RFE）和XGBoost等机器学习方法，确定二硫键介导的细胞焦亡相关基因NUBPL为胃癌的潜在预测因子。构建蛋白质-蛋白质相互作用（PPI）网络，并使用基因本体论（GO）数据库和京都基因与基因组百科全书（KEGG）数据库分析NUBPL在胃癌中的蛋白质相互作用和通路富集情况。同时，使用ESTIMATE算法进行免疫浸润分析和免疫治疗反应预测，并利用癌症药物敏感性基因组学（GDSC）数据库进行NUBPL的药物敏感性分析。采用分子生物学方法验证NUBPL在胃癌中的作用及其对二硫键介导的细胞焦亡的抑制作用。
NUBPL的异常表达显著影响胃癌的预后，并调节代谢和免疫相关通路。在NUBPL表达水平升高的患者中，CD8阳性T细胞数量减少与不良预后和胃癌进展相关。NUBPL表达水平升高会损害趋化因子的功能。此外，NUBPL表达水平较低的患者对免疫治疗表现出更好的反应。我们还确定了QS11、伊马替尼和AS601245等药物为NUBPL的潜在抑制剂。实验表明，NUBPL通过调节磷酸戊糖途径（PPP）和抑制二硫键介导的细胞焦亡来影响胃癌细胞的侵袭和迁移，而不是增殖和凋亡。
本研究强调了NUBPL在胃癌进展中的关键作用，并突出了其作为胃癌靶向治疗和免疫治疗潜在靶点的重要性。胃癌、NUBPL、二硫键介导的细胞焦亡、生物标志物、免疫治疗、机器学习
