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- W3202042679 abstract "Background: Colorectal cancer (CRC) is one of the high incidence tumors 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 tumor microenvironment. However, how cancer cells respond to this acidic environment surrounding them remains largely unknown, especially in colorectal cancer.Methods: Proton sensor receptor expression was analyzed 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 analyzed both in vitro and in vivo. Pharmacological intervention, immunofluorescence and gene set enrichment analyses were performed to reveal the underlying molecular mechanisms of GPR4.Findings: We found that GPR4 was upregulated in CRC samples. In addition, its high expression correlated with late stage tumors 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 tumor microenvironment and enhanced RhoA activation and F-actin rearrangement, leading to LATS activity inhibition, YAP1 nuclear translocation and oncogene transcription.Conclusions: The expression of GPR4 is upregulated in colorectal cancer and is associated with shorter overall survival time in CRCpatients. These findings reveal the novel roles of GPR4 in CRC progression and suggest GPR4 might be a new therapeutic target for CRC treatment.Funding Statement: This work was supported by the grant from the National Natural Science Foundation of China (No.81702300 & No.81873555).Declaration of Interests: The authors declare no potential conflicts of interest.Ethics Approval Statement: Study protocol that strictly in line with International Ethical Guidelines for Biomedical Research Involving Human Subjects was approved by the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. Patients that had received no anti-tumor therapy and signed written informed consent were enrolled in this study." @default.
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- W3202042679 date "2019-01-01" @default.
- W3202042679 modified "2023-09-27" @default.
- W3202042679 title "Increased Proton-Sensing Receptor GPR4 Signaling Promotes Colorectal Cancer Progression by Activating the Hippo Pathway" @default.
- W3202042679 doi "https://doi.org/10.2139/ssrn.3409282" @default.
- W3202042679 hasPublicationYear "2019" @default.
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