Perren Leonie, Busch Moana, Ruiz Pedro A, Malagola Ermanno, Baumeler Valeria, Foti Federica, Gross Adelina, Grütter Tobias, Edel Hendrik, Schuler Cordelia, Handler Kristina, De Lange Glenn, Arnold Isabelle C, de Vallière Cheryl, Seuwen Klaus, Hausmann Martin, Rogler Gerhard
Department of Gastroenterology and Hepatology, University Hospital of Zurich, University of Zurich, Zurich, Switzerland.
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
Mol Oncol. 2025 May 21;19(8):2196-211. doi: 10.1002/1878-0261.70045.
We aimed to understand the role of G protein-coupled receptor 4 (GPR4) in tumorigenesis. GPR4 is a pH-sensing receptor that is activated by acidic extracellular pH. GPR4 is expressed primarily in vascular endothelial cells (ECs). Intestinal tissue from patients with inflammatory bowel disease (IBD) shows increased expression of GPR4. Patients with IBD have a significantly increased risk of developing colorectal cancer (CRC). In the MC38 model, Gpr4-deficient mice showed significantly reduced tumor size and weight compared to wild-type (WT) mice. This effect correlated with a significant increase in IL2 protein and natural killer (NK)1.1 cells in tumor tissue in Gpr4 compared to WT. In the azoxymethane (AOM)/dextran sodium sulfate (DSS) model of CRC, Gpr4-deficient mice showed significantly reduced tumor progression and number of apurinic/apyrimidinic (AP) sites. Gpr4-deficient mice showed a significantly increased number of NKp46 cells in tumor tissue, and increased numbers of NK cells were confirmed by qPCR and flow cytometry. The absence of GPR4 significantly attenuated tumor progression in the colon of mice, and this result correlated with increased cytotoxic cell activity and reduced presence of tumor-associated macrophages and neutrophils. GPR4 represents a potential new target for therapeutic intervention.
我们旨在了解G蛋白偶联受体4（GPR4）在肿瘤发生中的作用。GPR4是一种pH感应受体，可被酸性细胞外pH激活。GPR4主要在血管内皮细胞（ECs）中表达。炎症性肠病（IBD）患者的肠道组织显示GPR4表达增加。IBD患者患结直肠癌（CRC）的风险显著增加。在MC38模型中，与野生型（WT）小鼠相比，Gpr4基因缺陷小鼠的肿瘤大小和重量显著降低。与WT相比，这种效应与Gpr4基因缺陷小鼠肿瘤组织中IL2蛋白和自然杀伤（NK）1.1细胞的显著增加相关。在CRC的氧化偶氮甲烷（AOM）/葡聚糖硫酸钠（DSS）模型中，Gpr4基因缺陷小鼠的肿瘤进展和无嘌呤/无嘧啶（AP）位点数量显著减少。Gpr4基因缺陷小鼠肿瘤组织中的NKp46细胞数量显著增加，通过qPCR和流式细胞术证实NK细胞数量增加。GPR4的缺失显著减弱了小鼠结肠中的肿瘤进展，这一结果与细胞毒性细胞活性增加以及肿瘤相关巨噬细胞和中性粒细胞数量减少相关。GPR4代表了一个潜在的治疗干预新靶点。
