Revealing Potential Therapeutic Targets in Gastric Cancer through Inflammation and Protein-Protein Interaction Hub Networks

Background: Gastric cancer (GC) ranks second in incidence and mortality among digestive system cancer, following colorectal cancer. Currently treatment options are limited, and the prognosis for GC remains poor. Methods: Four bulk RNA sequencing (RNA-seq) datasets and two single-cell RNA sequencing (scRNA-seq) datasets were downloaded from the Gene Expression Omnibus (GEO) database. Initially, we identified differentially expressed genes (DEGs). The intersection list of inflammatory response-related DEGs (IRR-DEGs) was utilized for enrichment analyses. Hub genes were extracted from the protein-protein interaction (PPI) network of DEGs, exploring their expression in the context of scRNA-seq landscapes and cell-cell communication. IRR hub DEGs were identified, and pathway and receptor-ligand pairs were analyzed at this gene level. Results: The analysis identified 69 DEGs in GC. Among these, 8 IRR-DEGs (SPP1, TIMP1, SERPINF1, TNFAIP6, LGALS1, LY6E, MSR1, and SELE) were closely associated with 19 types of immune cells and various lymphocytes. Of the 12 hub genes (SPP1, TIMP1, FSTL1, THY1, COL4A1, FBN1, ASPN, COL10A1, COL5A1, THBS2, LUM, and SPARC), their expression is significantly enhanced in stem cells, primarily involving communication with monocytes, and four prognostic-related genes were discovered. Two IRR hub DEGs indicated that the SPP1 signaling pathway, specifically the SPP1-CD44 ligand-receptor pairs, plays a critical role. Conclusion: We have collectively identified 18 genes that could serve as biomarkers for future GC targeting. The discovery of the SPP1-CD44 ligand-receptor axis not only elucidates a novel inflammatory signaling pathway driving tumor progression, but also provides a potential therapeutic target for disrupting cancer-stromal interactions. Importantly, these biomarkers lay the foundation for developing precision immunotherapies that target the inflammatory-immune axis in GC management.