PYCR1的泛癌分析及其对膀胱癌化疗和免疫治疗应答的潜在预测价值  

A pan-cancer analysis of PYCR1 and its predictive value for chemotherapy and immunotherapy responses in bladder cancer

作　　者：李煜桐 宋杏钰 孙蕊旭 董璇 刘宏伟 LI Yutong;SONG Xingyu;SUN Ruixu;DONG Xuan;LIU Hongwei(Laboratory of Urology,Affiliated Hospital of Guangdong Medical University,Zhanjiang 524001,China;The First School of Clinical Medicine,Guangdong Medical University,Zhanjiang 524023,China)

机构地区：[1]广东医科大学附属医院泌尿外科研究室,广东湛江524001 [2]广东医科大学第一临床医学院,广东湛江524023

出　　处：《南方医科大学学报》2025年第4期880-892,共13页Journal of Southern Medical University

基　　金：广东省基础与应用基础研究基金(2024A1515012742);广东医科大学大学生创新创业训练计划项目(GDMU2023048,GDMU2023355,S202410571048)。

摘　　要：目的基于生物信息学分析探究吡咯啉-5-羧酸还原酶-1(PYCR1)作为泛癌生物标志物的潜力,并探究其在膀胱癌(BLCA)中的表达、功能及临床意义。方法通过生物信息学分析PYCR1与泛癌患者预后、免疫微环境重塑、肿瘤突变负荷及微卫星不稳定性的关联。在TCGA-BLCA数据集中通过单因素和多因素回归分析PYCR1作为BLCA患者独立预后风险因素的潜力,并构建临床决策模型。利用IMvigor210中的BLCA队列鉴定PYCR1作为免疫治疗效果评估独立因子的潜力。基于pRRophetic药物库筛选PYCR1高表达时BLCA治疗耐受的潜在化疗药物。CMap-XSum算法和分子对接技术用于筛选并验证小分子PYCR1抑制剂。结果PYCR1高表达与多种肿瘤不良预后、免疫细胞浸润、肿瘤突变负荷及微卫星不稳定性显著相关(r>0.3)。PYCR1在BLCA中过表达,PYCR1高表达与BLCA预后差密切相关(HR:1.14,95%CI:1.02-1.68,P=0.006)。PYCR1高表达时西妥昔单抗、5-氟尿嘧啶、多柔比星等抗肿瘤药物IC50提高(P<0.0001)。结论PYCR1是癌症潜在的预后生物标志物和治疗靶点,PYCR1高表达是BLCA患者不良预后的独立危险因素,其具有良好的临床决策能力,是预测化疗药物敏感性和免疫治疗效果的指标。Objective To explore the potential of pyrroline-5-carboxylate reductase 1(PYCR1)as a pan-cancer biomarker and investigate its expression,function,and clinical significance in bladder cancer(BLCA).Methods Bioinformatics analysis was conducted to evaluate the associations of PYCR1 with prognosis,immune microenvironment remodeling,tumor mutation burden(TMB),and microsatellite instability(MSI)in cancer patients.Using the TCGA-BLCA dataset,univariate and multivariate regression analyses were performed to assess the potential of PYCR1 as an independent prognostic risk factor for BLCA,and a clinical decision model was constructed.The IMvigor210 cohort was utilized to evaluate the potential of PYCR1 for independently predicting the efficacy of immunotherapy.The pRRophetic was employed to screen candidate chemotherapeutic agents for treating BLCA with high PYCR1 expression.The CMap-XSum algorithm and molecular docking techniques were used to explore and validate small molecule inhibitors of PYCR1.Results A high expression of PYCR1 was significantly associated with poor prognosis,immune cell infiltration,TMB and MSI in various tumors(r>0.3).PYCR1 was overexpressed in BLCA,and high PYCR1 expression was closely related to poor prognosis in BLCA patients(HR:1.14,95%CI:1.02-1.68,P=0.006).The IC50 of the anti-cancer drugs cetuximab,5-fluorouracil,and doxorubicin increased significantly in BLCA cell lines with high PYCR1 expressions(P<0.0001).Conclusion High PYCR1 expression is an independent risk factor for poor prognosis in BLCA patients and can serve as a significant indicator for clinical decision-making as well as a marker for predicting sensitivity to chemotherapeutic agents and the efficacy of immunotherapy.

关 键 词：膀胱癌 吡咯啉-5-羧酸还原酶-1 免疫治疗 化疗药物敏感性 小分子PYCR1抑制剂 

分 类 号：R737.14[医药卫生—肿瘤]