Loss of proton‐sensing GPR4 reduces tumor progression in mouse models of colon cancer
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)...
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| Format: | Article |
| Language: | English |
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Wiley
2025-08-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.70045 |
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| author | Leonie Perren Moana Busch Pedro A. Ruiz Ermanno Malagola Valeria Baumeler Federica Foti Adelina Gross Tobias Grütter Hendrik Edel Cordelia Schuler Kristina Handler Glenn De Lange Isabelle C. Arnold Cheryl deVallière Klaus Seuwen Martin Hausmann Gerhard Rogler |
| author_facet | Leonie Perren Moana Busch Pedro A. Ruiz Ermanno Malagola Valeria Baumeler Federica Foti Adelina Gross Tobias Grütter Hendrik Edel Cordelia Schuler Kristina Handler Glenn De Lange Isabelle C. Arnold Cheryl deVallière Klaus Seuwen Martin Hausmann Gerhard Rogler |
| author_sort | Leonie Perren |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6aec37da8a644500af2139d8a34346af |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-6aec37da8a644500af2139d8a34346af2025-08-20T03:39:45ZengWileyMolecular Oncology1574-78911878-02612025-08-011982196221110.1002/1878-0261.70045Loss of proton‐sensing GPR4 reduces tumor progression in mouse models of colon cancerLeonie Perren0Moana Busch1Pedro A. Ruiz2Ermanno Malagola3Valeria Baumeler4Federica Foti5Adelina Gross6Tobias Grütter7Hendrik Edel8Cordelia Schuler9Kristina Handler10Glenn De Lange11Isabelle C. Arnold12Cheryl deVallière13Klaus Seuwen14Martin Hausmann15Gerhard Rogler16Department of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandInstitute of Experimental Immunology University of Zurich Zurich SwitzerlandInstitute of Experimental Immunology University of Zurich Zurich SwitzerlandInstitute of Experimental Immunology University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandDepartment of Gastroenterology and Hepatology University Hospital of Zurich, University of Zurich Zurich SwitzerlandWe 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.https://doi.org/10.1002/1878-0261.70045colorectal cancerGPR4inflammatory bowel diseasepH‐sensing G protein‐coupled receptors |
| spellingShingle | Leonie Perren Moana Busch Pedro A. Ruiz Ermanno Malagola Valeria Baumeler Federica Foti Adelina Gross Tobias Grütter Hendrik Edel Cordelia Schuler Kristina Handler Glenn De Lange Isabelle C. Arnold Cheryl deVallière Klaus Seuwen Martin Hausmann Gerhard Rogler Loss of proton‐sensing GPR4 reduces tumor progression in mouse models of colon cancer Molecular Oncology colorectal cancer GPR4 inflammatory bowel disease pH‐sensing G protein‐coupled receptors |
| title | Loss of proton‐sensing GPR4 reduces tumor progression in mouse models of colon cancer |
| title_full | Loss of proton‐sensing GPR4 reduces tumor progression in mouse models of colon cancer |
| title_fullStr | Loss of proton‐sensing GPR4 reduces tumor progression in mouse models of colon cancer |
| title_full_unstemmed | Loss of proton‐sensing GPR4 reduces tumor progression in mouse models of colon cancer |
| title_short | Loss of proton‐sensing GPR4 reduces tumor progression in mouse models of colon cancer |
| title_sort | loss of proton sensing gpr4 reduces tumor progression in mouse models of colon cancer |
| topic | colorectal cancer GPR4 inflammatory bowel disease pH‐sensing G protein‐coupled receptors |
| url | https://doi.org/10.1002/1878-0261.70045 |
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