Yuan ZhenMin, Yang XiaoYing, Huang JunJie, Wei JunRen, Tian Lei
Department of Gastrointestinal & Gland Surgery Division I, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Hepatobiliary and Endocrine Surgery Department, Beihai People's Hospital, Beihai, China.
Front Oncol. 2025 Sep 10;15:1599542. doi: 10.3389/fonc.2025.1599542. eCollection 2025.
Gastric cancer (GC) is a highly malignant tumor with a complex etiology. Most patients are diagnosed at an advanced stage with poor prognosis. The carboxypeptidase family is associated with progression in many cancers. Carboxypeptidase Z (CPZ) is a cellular matrix regulator. Corresponding studies on CPZ expression and the molecular mechanisms of GC prognosis and immunomodulation are lacking. We examined the influence of CPZ expression on the prognosis and immunomodulation of GC and the corresponding clinical significance.
CPZ gene expression in pan-cancer analysis was conducted using the Tumor Immune Estimation Resource (TIMER2.0) database. Differences in CPZ expression levels were investigated using 412 GC samples and 36 normal tissue samples from The Cancer Genome Atlas (TCGA) database. These results were validated using the Gene Expression Profiling Interactive Analysis (GEPIA2) and Gene Expression Omnibus (GEO) datasets GSE65801 and GSE103236. The prognostic and diagnostic value of CPZ expression in patients with GC was assessed using Kaplan-Meier plotter, the chi-square test, and the receiver operating characteristic (ROC). Genes with joint CPZ differential expression were identified for functional enrichment analysis according to TCGA-STAD database. The link between CPZ and immune cell infiltration, immune checkpoints, and fibroblasts was determined using CIBERSORT, single-sample gene set enrichment analysis, and the TIMER2.0 immuno-gene module. The tumor mutational burden and immunotherapy were analyzed using maftools and The Cancer Imaging Archive data. CPZ expression-related drug susceptibility was analyzed using R oncoPredict package and Wilcoxon tests. Differential CPZ expression in cancer and paracancerous tissues was verified using immunohistochemistry (IHC) and quantitative PCR (qPCR).
The analysis demonstrated significantly increased CPZ expression in GC tissues. The CPZ expression level was an independent GC prognostic factor of risk. CPZ expression influenced immune cell and fibroblast infiltration in the GC tumor microenvironment. Elevated CPZ expression led to patient resistance to common chemotherapeutic agents such as oxaliplatin, docetaxel, and cisplatin. IHC and qPCR demonstrated significantly increased CPZ expression in GC tissues.
Elevated CPZ expression in GC tissues affects patient survival prognosis and can increase immune cell infiltration, affecting the tumor microenvironment. CPZ may be a novel predictive biomarker associated with immune-modulated prognosis in GC.
胃癌（GC）是一种病因复杂的高度恶性肿瘤。大多数患者在晚期被诊断出来，预后较差。羧肽酶家族与多种癌症的进展相关。羧肽酶Z（CPZ）是一种细胞基质调节剂。目前缺乏关于CPZ表达以及GC预后和免疫调节分子机制的相应研究。我们研究了CPZ表达对GC预后和免疫调节的影响以及相应的临床意义。
使用肿瘤免疫评估资源（TIMER2.0）数据库对泛癌分析中的CPZ基因表达进行分析。使用来自癌症基因组图谱（TCGA）数据库的412份GC样本和36份正常组织样本研究CPZ表达水平的差异。这些结果使用基因表达谱交互式分析（GEPIA2）以及基因表达综合数据库（GEO）数据集GSE65801和GSE103236进行验证。使用Kaplan-Meier绘图仪、卡方检验和受试者工作特征（ROC）评估CPZ表达在GC患者中的预后和诊断价值。根据TCGA-STAD数据库鉴定与CPZ差异表达相关的基因，进行功能富集分析。使用CIBERSORT、单样本基因集富集分析和TIMER2.0免疫基因模块确定CPZ与免疫细胞浸润、免疫检查点和成纤维细胞之间的联系。使用maftools和癌症影像存档数据对肿瘤突变负荷和免疫治疗进行分析。使用R语言oncoPredict包和Wilcoxon检验分析与CPZ表达相关的药物敏感性。使用免疫组织化学（IHC）和定量PCR（qPCR）验证癌症组织和癌旁组织中CPZ的差异表达。
分析表明GC组织中CPZ表达显著增加。CPZ表达水平是GC风险的独立预后因素。CPZ表达影响GC肿瘤微环境中的免疫细胞和成纤维细胞浸润。CPZ表达升高导致患者对奥沙利铂、多西他赛和顺铂等常用化疗药物产生耐药性。IHC和qPCR显示GC组织中CPZ表达显著增加。
GC组织中CPZ表达升高影响患者生存预后，并可增加免疫细胞浸润，影响肿瘤微环境。CPZ可能是一种与GC免疫调节预后相关的新型预测生物标志物。
