Novel perceptions of the involvement of CPZ in gastric cancer prognosis and immunomodulation.

[BACKGROUND] 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.

[METHODS] 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).

[RESULTS] 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.

[CONCLUSION] 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.