Frontiers in immunology · 2026
A palmitoylation-associated three-gene signature predicts prognosis, immune features, and drug sensitivity in gastric cancer: functional validation of CTHRC1.
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Sheng Hongmei, Li Xuejun, Zhang Chen, Song Miaomiao, Xu Juan, Ma Jun
Аннотация
BACKGROUND: Gastric cancer (GC) is a heterogeneous malignancy that requires improved molecular tools for prognostic stratification. Protein palmitoylation regulates membrane localization and signaling, but the clinical relevance of palmitoylation-related genes (PRGs) in GC remains unclear.
METHODS: Gene Expression Omnibus, The Cancer Genome Atlas, and GeneCards data were integrated to identify PRGs. Differential expression analysis, weighted gene co-expression network analysis, and three machine-learning algorithms were used to select key genes. Diagnostic and prognostic performance was evaluated in TCGA-STAD, platform-specific GEO cohorts, and an institutional cohort of 80 paired tissues. Immune infiltration, single-cell RNA sequencing, immunotherapy-related indices, and GDSC-based drug sensitivity were analyzed. CTHRC1 was further examined using clinical specimens, cell assays, and xenografts.
RESULTS: Thirteen differentially expressed PRGs were identified, and SERPINE1, CTHRC1, and EGR1 were selected. The integrated diagnostic model achieved AUCs of 0.935 in TCGA-STAD, 1.000 in GSE54129, and 0.916 in GSE118916, respectively. The three-gene score stratified overall survival in the total, training, and testing TCGA-STAD cohorts and in GSE84437, GSE236522, and the institutional cohort. It remained independently associated with survival in multivariable analysis. High-risk tumors showed increased stromal and immune scores, altered immune-cell composition, higher checkpoint expression, and higher TIDE scores. Single-cell analysis localized SERPINE1 and CTHRC1 mainly to fibroblast-related compartments. CTHRC1 knockdown reduced GC-cell proliferation, clonogenicity, migration, invasion, and xenograft growth while increasing apoptosis.
CONCLUSION: The SERPINE1/CTHRC1/EGR1 signature provides prognostic and immune-stromal information in GC, and the experiments support a tumor-promoting role for CTHRC1. The findings define a palmitoylation-associated transcriptional framework but do not establish a palmitoylation-dependent mechanism.
METHODS: Gene Expression Omnibus, The Cancer Genome Atlas, and GeneCards data were integrated to identify PRGs. Differential expression analysis, weighted gene co-expression network analysis, and three machine-learning algorithms were used to select key genes. Diagnostic and prognostic performance was evaluated in TCGA-STAD, platform-specific GEO cohorts, and an institutional cohort of 80 paired tissues. Immune infiltration, single-cell RNA sequencing, immunotherapy-related indices, and GDSC-based drug sensitivity were analyzed. CTHRC1 was further examined using clinical specimens, cell assays, and xenografts.
RESULTS: Thirteen differentially expressed PRGs were identified, and SERPINE1, CTHRC1, and EGR1 were selected. The integrated diagnostic model achieved AUCs of 0.935 in TCGA-STAD, 1.000 in GSE54129, and 0.916 in GSE118916, respectively. The three-gene score stratified overall survival in the total, training, and testing TCGA-STAD cohorts and in GSE84437, GSE236522, and the institutional cohort. It remained independently associated with survival in multivariable analysis. High-risk tumors showed increased stromal and immune scores, altered immune-cell composition, higher checkpoint expression, and higher TIDE scores. Single-cell analysis localized SERPINE1 and CTHRC1 mainly to fibroblast-related compartments. CTHRC1 knockdown reduced GC-cell proliferation, clonogenicity, migration, invasion, and xenograft growth while increasing apoptosis.
CONCLUSION: The SERPINE1/CTHRC1/EGR1 signature provides prognostic and immune-stromal information in GC, and the experiments support a tumor-promoting role for CTHRC1. The findings define a palmitoylation-associated transcriptional framework but do not establish a palmitoylation-dependent mechanism.