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Review
. 2023 Jan 25;15(3):736.
doi: 10.3390/cancers15030736.

An Update of G-Protein-Coupled Receptor Signaling and Its Deregulation in Gastric Carcinogenesis

Huan Yan  1   2   3 , Jing-Ling Zhang  1   2   3 , Kam-Tong Leung  4 , Kwok-Wai Lo  1 , Jun Yu  2   5 , Ka-Fai To  1   2 , Wei Kang  1   2   3
Affiliations
Review

An Update of G-Protein-Coupled Receptor Signaling and Its Deregulation in Gastric Carcinogenesis

Huan Yan et al. Cancers (Basel). .

Abstract

G-protein-coupled receptors (GPCRs) belong to a cell surface receptor superfamily responding to a wide range of external signals. The binding of extracellular ligands to GPCRs activates a heterotrimeric G protein and triggers the production of numerous secondary messengers, which transduce the extracellular signals into cellular responses. GPCR signaling is crucial and imperative for maintaining normal tissue homeostasis. High-throughput sequencing analyses revealed the occurrence of the genetic aberrations of GPCRs and G proteins in multiple malignancies. The altered GPCRs/G proteins serve as valuable biomarkers for early diagnosis, prognostic prediction, and pharmacological targets. Furthermore, the dysregulation of GPCR signaling contributes to tumor initiation and development. In this review, we have summarized the research progress of GPCRs and highlighted their mechanisms in gastric cancer (GC). The aberrant activation of GPCRs promotes GC cell proliferation and metastasis, remodels the tumor microenvironment, and boosts immune escape. Through deep investigation, novel therapeutic strategies for targeting GPCR activation have been developed, and the final aim is to eliminate GPCR-driven gastric carcinogenesis.

Keywords: G protein; G-protein-coupled receptor; gastric cancer; targeted therapy.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
The structure GPCRs and their dysregulation in GC (*, Conserved motifs). GPCRs are widely expressed in the stomach. GPCRs participate in a variety of physiological and pathological processes. The upregulated GPCRs, including PAR1, CXCR4 and P2YR, and BILF1, are identified in GC. The five key sequence motifs in the class A GPCRs represent the most frequent mutant sites, which are conserved and responsible for their structural integrity and essential function. Abbreviations: GC, gastric cancer; PAR1, Protease-activated receptor 1; CXCR4, Chemokine CXC receptor 4; P2YR, P2Y receptor.
Figure 2
Figure 2
GPCR signaling and its crosstalk with other signaling pathways. (A) The most common GPCR-related signaling pathways. Agonist-stimulated GPCRs undergo a conformational change and facilitate the dissociation of Gα/Gβγ heterotrimer by replacing GDP with GTP on the Gα subunit. Subsequently, Ga and Gβγ trigger several downstream effectors, including secondary messenger systems, GEFs, Rho, and Ras GTPases, leading to a wide range of biological regulation. Besides the regulators of the G protein, signaling proteins (RGS proteins) promote the heteromeric complex reassociation and the signaling termination by accelerating intrinsic GTPase activity. Notably, agonist-activated GPCRs are also phosphorylated by GRKs and interact with β-arrestin, resulting in signaling desensitization and GPCR endocytosis. The endocytic β-arrestin-GPCR complex can be modulated by multiple factors and undergo degradation or recycling. (B) GPCR-associated crosstalk on the membrane and GPCR-EGFR crosstalk contain EGFR ligand-dependent transactivation and EGFR ligand-independent transactivation. The following pathways are the Wnt and Shh pathways. (C) The main pathways targeted by the multiple effectors in (a) consist of the following signaling pathways: Hippo pathway, MAPK pathway, Shh pathway, and Wnt pathway. Abbreviations: AC, adenylyl cyclase; AKT, protein kinase B; CREB, cAMP response element-binding protein; EGF, epidermal growth factor; EGFR, EGF receptor; ERK, extracellular signal-regulated kinase; GEF, guanine exchange factor; GLI, glioma-associated oncogenes; GPCR, G protein-coupled receptor; GRK, G protein-coupled receptor kinase; JNK, c-jun N-terminal kinase; LATS, large tumor suppressor kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PDEs, phosphodiesterases; PI3K, phosphatidylinositol-3-kinase; PKA, Protein Kinase A; PLCβ, Phospholipase C β; ROCK, Rho-associated protein kinase; Shh, sonic hedgehog protein; SMO, Smoothened protein; SuFu, suppressor of fused; TAZ, transcriptional coactivator with PDZ-binding motif; TCF/LEF, T-cell factor/lymphoid enhancer factor; TEAD, transcriptional enhanced associate domain; YAP, yes-associated protein.
Figure 3
Figure 3
GPCR-mediated metastasis and tumor microenvironment remodeling in GC. (A) The TME of GC consists of blood vessels, lymph vessels, immune cells, stromal cells (including fibroblast, pericytes, and adipocytes), extracellular matrix (ECM), and secreted soluble factors, such as proteins, RNAs, and small organelles. (B) GPCRs control the process of angiogenesis and metastasis. GPCR activation drives the production of stimulatory angiogenic factors like VEGF and EGF. These factors promote the development of new blood vessels by modulating the mitogenesis, migration, and sprouting of endothelial cells (ECs). Moreover, several GPCRs regulate the metastasis process by influencing ECM, degrading the status of cancer cells (EMT, migration, and invasion), and colonizing foreign sites. (C) Chemokine–chemokine receptors modulate immune responses. The chemokines are secreted by tumor cells, immune cells, and stromal cells. The interaction of chemokine and specific chemokine receptors recruits antitumor immune cells and immunosuppressive immune cells into the tumor microenvironment.
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