摘要
目的探索驱动程序性死亡受体-1(PD-1)耐药的关键分子机制,寻找错配修复正常(pMMR)/微卫星稳定(MSS)型胃癌的疗效预测标志物。方法选取医院2021年1月1日至2024年12月31日收治的经病理确诊且行根治术的pMMR/MSS型胃癌患者10例,根据患者预后的不同分为临床获益[完全缓解(CR)+部分缓解(PR)+疾病稳定(SD)]组和疾病进展组(PD组),各5例。收集患者术后标本,采用定量蛋白质组学技术[串联质谱标签(TMT)+滤膜辅助样品制备技术(FASP)],结合生物信息学方法分析其中关键的蛋白和分子机制,探讨候选分子的功能机制,筛选潜在靶点。结果两组共鉴定出336个差异表达蛋白,其中168个上调、168个下调,腺嘌呤核苷酸转运蛋白2(ANT2)显著上调,并伴随谷胱甘肽过氧化物酶3(GPX3)和超氧化物歧化酶3(SOD3)显著下调。基因本体论(GO)分析结果显示,线粒体功能障碍和氧化还原失衡可能是PD-1耐药的重要机制。京都基因和基因组数据库(KEGG)通路富集分析结果显示,主要涉及铁死亡、脂肪酸代谢、氨基酸代谢、细胞衰老、白细胞介素17信号、过氧化物酶体等通路,其中铁死亡通路较显著,这与GO分析中氧化应激相关通路的富集结果相互印证。结论ANT2上调与氧化应激通路异常可能共同促成PD-1耐药,可为pMMR型胃癌联合治疗策略的制订提供新靶点。
Objective To explore the key molecular mechanisms of driving-programmed death-1(PD-1)resistance,and to identify predictive biomarkers of therapeutic efficacy in patients with gastric cancer with proficient mismatch repair(pMMR)/microsatellite stable(MSS)type.Methods Ten patients with pMMR/MSS gastric cancer who were pathologically confirmed and underwent radical surgery from January 1,2021 to December 31,2024 were selected.Based on their prognostic outcomes,the patients were divided into the clinical benefit[complete response(CR)+partial response(PR)+stable disease(SD)]group and the progression disease(PD)group,with five cases in each group.The patients′postoperative specimens were collected,the key proteins and molecular mechanisms were analyzed by the quantitative proteomics techniques[tandem mass tag(TMT)+filter-aided sample preparation(FASP)]combined with bioinformatics method,the functional mechanisms of candidate molecules were investigated,and the potential therapeutic targets were screened.Results A total of 336 differentially expressed proteins were identified,including 168 up-regulated and 168 down-regulated proteins.The adenine nucleotide translocator 2(ANT2)significantly up-regulated,and the glutathione peroxidase 3(GPX3)and superoxide dismutase 3(SOD3)significantly downregulated.Gene Ontology(GO)analysis showed that the important mechanisms of inducing PD-1 resistance might be mitochondrial dysfunction and redox imbalance.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analysis enriched ferroptosis,fatty acid metabolism,amino acid metabolism,cellular senescence,interleukin-17 signaling,and peroxisome pathways,etc.Among these,the ferroptosis pathway was particularly prominent,which was consistent with the enrichment results of oxidative stress-related pathways in the GO analysis.Conclusion The upregulation of ANT2 and the abnormalities of oxidative stress pathways may collectively induce PD-1 resistance,which provide novel targets for establishing combination therapy strategies for the tratment of pMMR gastric cancer.
作者
金蕊
郭甲民
丁彩霞
王晓敏
赵培西
JIN Rui;GUO Jiamin;DING Caixia;WANG Xiaomin;ZHAO Peixi(Shaanxi Provincial Cancer Hospital,Xi'an,Shaanxi 710061,China;Xi'an Jiaotong University Health Science Center,Xi'an,Shaanxi 710061,China)
出处
《中国药业》
2026年第9期40-45,共6页
China Pharmaceuticals
基金
陕西省西安市科技计划项目[23YXYJ0136,24LLRHZDZX0023]。
