ArticleEBioMedicine2019
Increased proton-sensing receptor GPR4 signalling promotes colorectal cancer progression by activating the hippo pathway.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 48 citations in OpenAlex.
- Unveiling the impact of colonic pH and pH-sensing receptors in blood pressure regulation.Gut microbes · 2026Review
- GPR4 promotes immune exclusion in colon cancer through LOXL2-mediated extracellular matrix remodeling.Nature communications · 2025Article
- Low pH, High Stakes: A Narrative Review Exploring the Acid-Sensing GPR65 Pathway as a Novel Approach in Renal Cell Carcinoma.Cancers · 2025Review
- Loss of proton-sensing GPR4 reduces tumor progression in mouse models of colon cancer.Molecular oncology · 2025Article
- The Use of Biologics for Targeting GPCRs in Metastatic Cancers.Biotech (Basel (Switzerland)) · 2025Review
- Hippo/YAP signaling pathway in colorectal cancer: regulatory mechanisms and potential drug exploration.Frontiers in oncology · 2025Review
- Review
- Acid-sensing receptor GPR4 plays a crucial role in lymphatic cancer metastasis.Cancer science · 2024Article
- Role of pH-sensing receptors in colitis.Pflugers Archiv : European journal of physiology · 2024Review
- cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment.Journal of hematology & oncology · 2024Review
- Proton Sensing GPCR's: The missing link to Warburg's Oncogenic Legacy?Journal of cancer biology · 2024Article
- Article
- circ_0014736 induces GPR4 to regulate the biological behaviors of human placental trophoblast cells through miR-942-5p in preeclampsia.Open medicine (Warsaw, Poland) · 2023Article
- Protons taken hostage: Dynamic H-bond networks of the pH-sensing GPR68.Computational and structural biotechnology journal · 2023Article
- Physiological relevance of proton-activated GPCRs.Pflugers Archiv : European journal of physiology · 2022Review
- Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression.Reviews of physiology, biochemistry and pharmacology · 2022Review
- Proton-Sensing GPCRs in Health and Disease.Cells · 2021Review
- Data mining combined with experiments to validate CEP55 as a prognostic biomarker in colorectal cancer.Immunity, inflammation and disease · 2021Article
- GPR4 signaling is essential for the promotion of acid-mediated angiogenic capacity of endothelial progenitor cells by activating STAT3/VEGFA pathway in patients with coronary artery disease.Stem cell research & therapy · 2021Article
- Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundColorectal cancer (CRC) is one of the high incidences tumours and is ranked second in cancer-related mortality. Even though great progress has been made, there are no effective therapeutic strategies for late stage and metastatic CRC patients. Acidity is one characteristic of the tumour microenvironment. However, how cancer cells respond to this acidic environment surrounding them remains largely unknown, especially in colorectal cancer.
methodsProton sensor receptor expression was analysed in GEO and TCGA datasets. The expression of GPR4 in CRC specimens was confirmed by western blotting and immunohistochemistry (IHC). The role of GPR4 in CRC progression was analysed both in vitro and in vivo. Pharmacological intervention, immunofluorescence and gene set enrichment analyses were performed to reveal the underlying molecular mechanisms of GPR4.
findingsWe found that GPR4 was upregulated in CRC samples. In addition, its high expression correlated with late stage tumours and poor overall survival in patients. Furthermore, loss-of-function assays proved that GPR4 promoted CRC carcinogenesis and metastatic ability. Mechanistically, GPR4 was activated by extracellular protons in the tumour microenvironment and enhanced RhoA activation and F-actin rearrangement, leading to LATS activity inhibition, YAP1 nuclear translocation and oncogene transcription.
interpretationThe expression of GPR4 is upregulated in colorectal cancer and is associated with shorter overall survival time in CRC patients. These findings reveal the novel roles of GPR4 in CRC progression and suggest GPR4 might be a new therapeutic target for CRC treatment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.