Role of G Protein-Coupled Estrogen Receptor in Digestive System Carcinomas: A Minireview

Figures & data

Table 1 Summary of the Role of GPER in Various Digestive System Malignancies

Types	GPER Expression*	Function	Ligand	Signaling Pathways	Study Objects	Reference
GC	Down-regulated	Predict good prognosis	Non-specified	EMT	Bioinformatics Clinical samples In vitro	[^Citation76]
	Down-regulated	Increase cell death	G1	ER stress	Clinical In vitro In vivo	[^Citation77]
	Up-regulated	Predict poor prognosis	Non-specified	Non-specified	Bioinformatics	[^Citation78]
HCC	Non-specified	Regulate iron metabolism	E2; G1 ICI 182720	GPR30/BMP6	In vitro In vivo	[^Citation85]
	Non-specified	Antiviral	E2; G1; G15 tamoxifen	GPR30/MMP9	In vitro	[^Citation86]
	Non-specified	Mechanical reprogramming	Tamoxifen	GPER/RhoA/myosin	In vitro	[^Citation87]
	Non-specified	Inhibit proliferation; Stimulate apoptosis	E2; G1	GPER/ERK	In vitro	[^Citation88]
	Down-regulated	Regulate inflammatory responses	G1	Non-specified	Clinical samples In vitro In vivo	[^Citation69]
	Up-regulated	Promote tumor development	E2	GPER/PI3K/AKT/mTOR	Clinical samples In vivo	[^Citation89]
	Non-specified	Increase miR-21 transcription	DHEA; G1; G15 ICI 182720	GPER/ERK	In vitro	[^Citation90]
	Non-specified	Up-regulate FASN; Increase cell growth	E2; G1	GPER/ERK/c-fos/AP-1	In vitro	[^Citation92]
PDAC	Non-specified	Sensitize cells to chemotherapy	AXP107-11 G1; G15	GPER/MAPK	Bioinformatics In vitro In vivo	[^Citation96]
	Non-specified	Inhibit mechanotransduction and invasion	G1 G15	GPER/PKA/RhoA/myosin2	Bioinformatics In vitro	[^Citation97]
	Non-specified	Induce tumor regression; Increase cell immunogenicity	G1	Non-specified	Clinical samples In vitro In vivo	[^Citation72]
	Non-specified	Reprogram the tumor Microenvironment; Increase apoptosis	Tamoxifen	GPER/HIF-1α	In vitro In vivo	[^Citation99]
	Non-specified	Mechanically regulate the tumor microenvironment	Tamoxifen	GPER/RhoA	In vitro In vivo	[^Citation100]
CRC	Down-regulated	Inhibit proliferation; Induce cell cycle arrest; Increase the mitochondrial related apoptosis	G1	GPER/ROS/ERK1/2 GPER/KKα/IκBα/NF-κB GPER/GSK-3β/NF-κB	Bioinformatics Clinical samples In vitro In vivo	[^Citation102]
	Up-regulated (hypoxia)	Induce cell migration and proliferation (hypoxia); Suppress cell migration and proliferation (normoxia)	E2	GPER/HIF-1α GPER/VEGFA	Bioinformatics In vitro	[^Citation105]
	Non-specified	Hydrolyze E1S	E2; G1 tamoxifen ICI 182780	GPER/STS	In vitro	[^Citation106]
	Up-regulated	Augment proliferation; Predict poor outcomes	E2; G1; G15	Non-specified	Bioinformatics In vitro In vivo	[^Citation107]
	Non-specified	Up-regulate FASN; Increase cell growth	E2; G1	GPER/ERK/c-fos/AP-1	In vitro	[^Citation92]

Note: *GPER expression levels in tumor tissues or cells compared to those in normal tissues and cells.

Abbreviations: AXP107-11, a genistein analogue; CRC, colorectal cancer; DHEA, dehydroepiandrosterone; GC, gastric cancer; HCC, hepatocellular carcinoma; IκB, inhibitor of nuclear factor-κB; IKK, IkappaB kinase; MAPK, mitogen-activated protein kinases; mTOR, mammalian target of rapamycin; PDAC, pancreatic ductal adenocarcinoma; PKA, protein kinase A; ROS, reactive oxygen species; VEGFA, vascular endothelial growth factor A.

Table 2 Summary of the Type of GPER Ligands

Steroid Hormones	SERDs/SERMs	Synthetic Estrogens	Phytoestrogens	Synthetic Compounds
17β-estradiol	ICI182780	Bisphenols	Quercetin	G1
17α-estradiol	Tamoxifen	Methoxychlor	Genistein	G15
Estrone	Raloxifene	Alkylphenols	Daidzein	G36
Estriol		Polychlorinated biphenyls	Resveratrol	CIMBA
		Dioxins	Oleuropein
		Phthalates	Hydroxytyrosol

Figure 1 Schematic diagram of the GPER signaling pathways. Once the binding of the agonist is generated, GPER can induce heterotrimeric G proteins, resulting in multiple downstream events, including AC/cAMP/PKA/CREB, Src, and SphK. MMP, activated by the latter two signals, may cleave pro-HB-EGF and liberate free HB-EGF, which in turn transactivates EGFR. Subsequently, EGFR activation appears to be involved in the activation of MAPK/ERK and PI3K/AKT pathways. Additionally, the additional signals activated by GPER include PLC/IP3/calcium mobilization, PKC, and Hippo/YAP signaling.

Abbreviations: AC, adenylyl cyclase; CREB, cAMP response element binding protein; IP3, inositol triphosphate; MAPK, mitogen-activated protein kinases; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; YAP, Yes-associated protein.

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