{
  "abstract": "Introduction Gastric cancer remains a leading cause of cancer morbidity and mortality worldwide, and although immunotherapy has revolutionized cancer treatment, its efficacy in gastric cancer remains limited due to the complex tumor immune microenvironment. As a GPCR, GPRC5A has been implicated in tumorigenesis across cancers, but its role in gastric cancer progression and immune modulation is uncharacterized.Methods GPRC5A expression in gastric cancer and normal gastric mucosa, and its association with overall survival (OS) was analyzed based on public multi-omics data. CCK-8 assay, colony formation experiment, wound-healing assay, Transwell assay with or without Matrigel, and subcutaneous xenograft models in nude mice were employed to evaluate the effects of GPRC5A on the proliferation, migration and invasion of gastric cancer cells in vitro and in vivo. For mechanism, gene set enrichment analysis (GESA) were performed following Western blot validation. At last, correlations between GPRC5A expression and tumor purity, immune-infiltration scores, and immune cell infiltration were assessed in gastric cancer samples to explore the immunological relevance.Results Clinically, GPRC5A was significantly overexpressed in gastric cancer tissues compared to normal mucosa, and high expression correlated with worse OS (P < 0.01). In terms of function, GPRC5A knockdown significantly reduced the proliferative activity and colony-forming ability of gastric cancer cells. Similarly, the wound-healing rate in the GPRC5A knockdown group, as well as the number of cells that migrated or invaded through Transwell chambers, was significantly lower than that in the control group. In vivo, tumors from GPRC5A-silenced cells grew more slowly and were significantly smaller in volume and weight. Mechanistically, GSEA indicated enrichment of STAT3 signaling in GPRC5A high-expression tumors, and furher Western blot confirmed reduced phospho-STAT3 upon GPRC5A knockdown, suggesting activation of STAT3 by GPRC5A. For tumor microenvironment, immune analyses indicated that tumors with high GPRC5A expression were characterized by elevated tumor purity but concurrently exhibited decreased immune infiltration scores and diminished levels of multiple immune effector cells, implying a suppressed immune-killing function within these tumors. Cell–cell communication analysis showed enhanced ligand–receptor interactions in GPRC5A-high tumors involving collagen, laminin, MIF, and other pro-tumorigenic pathways.Conclusions This study elucidates that GPRC5A drived gastric cancer progression by STAT3 activation and was closely associated with immune-suppressive tumor microenvironment. Targeting GPRC5A might be a promising strategy for effective GC management. Further validation in clinical cohorts and exploration of combined GPRC5A-targeted and immunotherapy approaches are warranted.",
  "authors": [
    {
      "affiliations": [
        "The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China"
      ],
      "name": "Chenyu Yang"
    },
    {
      "affiliations": [
        "The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China"
      ],
      "name": "Qinglin Zhang"
    },
    {
      "affiliations": [
        "The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China"
      ],
      "name": "Qiang Zhan"
    }
  ],
  "title": "O17 GPRC5A drived gastric cancer progression and associated with immune-suppressive tumor microenvironment",
  "uid": "358daef0-4ecb-5195-a60f-39780078dbac"
}