Increased proton-sensing receptor GPR4 signalling promotes colorectal cancer progression by activating the hippo pathway

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.

Identification of a 9-Gene Prognostic signature for breast cancer

“…In the brains of patients with Alzheimer's disease, PNMT protein at the axon end is reduced due to reduced transport of PNMT [32]. Zhong M's research found that the proton-sensing receptor GPR4 is highly expressed in colorectal cancer (CRC) and promotes the metastasis of CRC cells by inhibiting LATS activity and YAP1 nuclear translocation [33]. Chen Z's research showed that DARPP-32 can further regulate the angiogenic effect of ANGPT2 by inducing STAT3 phosphorylation in gastric tumors [34].…”

Metabolite Sensing GPCRs: Promising Therapeutic Targets for Cancer Treatment?

“…GPR4 appeared up-regulated in cholangiocarcinoma, down-regulated in cervical and lung cancers, and increased or decreased in kidney tumors depending on the kind of cancer [150]. Analysis centered in particular cancers revealed the up-regulated expression of GPR4 in head and neck squamous cell carcinoma [151], in renal cell carcinoma [152], in colorectal cancer [153] and in hepatocellular carcinoma [154] and, in most of these studies, its high expression correlated with late stage tumors and poor overall survival [152][153][154][155].…”

“…Functional studies show divergent roles of GPR4 in different types of cancer. On one hand, GPR4-knock out (KO) mice showed reduced tumorigenesis after the orthotropic transplantation of cells from murine breast (4T1) or colon cancer (CT26) cell lines [156] while suppression of GPR4 in human colorectal cancer (HCT116) cells significantly attenuated tumor growth of subcutaneous xenografts and reduced liver invasion in a metastasis model in nude mice [153]. This protumoral effect may be related with a proangiogenic activity since colonic tumors from GPR4-KO mice presented an altered vessel morphology, length and density [156] and GPR4-transfected cells promoted the formation of tubes by human microvascular endothelial cells in a paracrine manner in vitro [151].…”

Role of Sphingosylphosphorylcholine in Tumor and Tumor Microenvironment

“…Recently, encouraging reports outlined the importance of the GPR4 gene itself in diseases, independent of SPC. GPR4 is also involved in the progression of head and neck cancer, epithelial ovarian cancer (EOC) and colorectal cancer [58,59]. A positive correlation between GPR4 expression and a higher microvascular density in EOC was observed, but this was not evident in benign ovarian tumor tissues [60].…”