A Pan-Cancer and Integrated Bioinformatic Analysis Identifies RGS4 as a Novel Prognostic and Immunological Biomarker in Gastric Cancer

Abstract

Background: The Regulator of G-protein signaling 4 (RGS4) plays a context-dependent role in various cancers. However, its comprehensive prognostic and immunological implications in gastric cancer (GC) remain largely unexplored.

Methods: We systematically analyzed RGS4 expression using multiple independent cohorts, including TCGA-STAD, GSE84426, and GSE15459. Protein expression was validated using CPTAC data via UALCAN. Survival analyses (OS and PFS) were conducted in the TCGA cohort. Functional enrichment analyses (GO, KEGG, and GSEA) were performed on genes co-expressed with RGS4. A prognostic nomogram integrating RGS4 and clinical parameters was developed and validated. Finally, we expanded our analysis to a pan-cancer level to assess RGS4's expression and prognostic value across 33 cancer types.

Results: RGS4 was significantly overexpressed in GC tissues at both mRNA and protein levels. High RGS4 expression was strongly associated with poorer overall survival (HR = 1.75, 95% CI: 1.25–2.45, p = 0.001) and progression-free survival(HR = 1.45, 95% CI: 1.02–2.07, p = 0.040). Functional analysis revealed that RGS4 co-expressed genes were primarily enriched in immune-related pathways and cell migration. The nomogram, incorporating RGS4 and TNM stage, demonstrated good predictive accuracy for 1-, 3-, and 5-year survival (C-index = 0.69). Pan-cancer analysis revealed that RGS4 was dysregulated in multiple cancers and served as a risk factor in several malignancies, including LIHC and KIRC.

Conclusion: Our multi-faceted study establishes RGS4 as a robust prognostic biomarker in GC, intricately linked to tumor immunity. Its dysregulation and prognostic value across various cancers suggest a broad oncogenic role, positioning it as a potential therapeutic target.