Lin Jiahui, Ke Lingling, Cheng Sha, Lu Wei, Hu Yanan, He Xiyi, Luo Tingting, Liu Yuting, Xu Canxia, Qi Jian
Digestive Diseases Center, Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, Guangdong 518107, China.
Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, China.
Mediators Inflamm. 2025 Jul 11;2025:7977933. doi: 10.1155/mi/7977933. eCollection 2025.
Orphan class A G protein-coupled receptors (GPCRs) are a large and diverse family with broad tissue expression, and their roles in tumors are increasingly recognized. However, their involvement in gastric cancer (GC) remains unclear. We performed survival and differential expression analyses to characterize orphan class A GPCR expression patterns in stomach adenocarcinoma (STAD). A prognostic risk model was developed using univariate Cox and LASSO regression analysis and validated in the GEO database. Drug sensitivity and immune infiltration were evaluated across different risk groups. The role of GPR176 in GC and its relationship with tumor immunity were further explored using cellular assays. A model incorporating nine orphan class A GPCRs (GPR15, GPR150, GPR176, GPR4, GPR26, GPR78, GPR101, GPR34, and GPR87) was constructed, showing a positive correlation with M2 macrophages and naive B cells. Low-risk patients showed higher sensitivity to AZD6482, BX.795, GDC0941, and pazopanib. GPR176 was found to be upregulated in GC, and functional assays demonstrated that its knockdown suppressed proliferation and migration in the GC cell lines SGC-7901 and HGC-27. GPR176 also modulated the Wnt/β-catenin pathway and M2 macrophage polarization. These findings may provide new insights into the role of orphan class A GPR genes in STAD and identify GPR176 as a new therapeutic target for GC.
孤儿A类G蛋白偶联受体（GPCRs）是一个庞大且多样的家族，具有广泛的组织表达，其在肿瘤中的作用日益受到认可。然而，它们在胃癌（GC）中的作用仍不清楚。我们进行了生存和差异表达分析，以表征胃腺癌（STAD）中孤儿A类GPCR的表达模式。使用单变量Cox和LASSO回归分析建立了一个预后风险模型，并在GEO数据库中进行了验证。评估了不同风险组之间的药物敏感性和免疫浸润情况。使用细胞实验进一步探讨了GPR176在GC中的作用及其与肿瘤免疫的关系。构建了一个包含9个孤儿A类GPCR（GPR15、GPR150、GPR176、GPR4、GPR26、GPR78、GPR101、GPR34和GPR87）的模型，该模型与M2巨噬细胞和幼稚B细胞呈正相关。低风险患者对AZD6482、BX.795、GDC0941和帕唑帕尼表现出更高的敏感性。发现GPR176在GC中上调，功能实验表明，敲低它可抑制GC细胞系SGC-7901和HGC-27的增殖和迁移。GPR176还调节Wnt/β-连环蛋白信号通路和M2巨噬细胞极化。这些发现可能为孤儿A类GPR基因在STAD中的作用提供新的见解，并将GPR176确定为GC的一个新的治疗靶点。
