G protein-coupled estrogen receptor stimulates human trophoblast cell invasion via YAP-mediated ANGPTL4 expression

AbstractInsufficient invasion of trophoblast cells into the uterine decidua is associated with preeclampsia (PE). G protein-coupled estrogen receptor (GPER) is a membrane estrogen receptor involved in non-genomic estrogen signaling. GPER is expressed in human trophoblast cells and downregulated GPER levels are noted in PE. However, to date, the role of GPER in trophoblast cells remains largely unknown. Here, we applied RNA sequencing (RNA-seq) to HTR-8/SVneo human trophoblast cells in response to G1, an agonist of GPER, and identified angiopoietin-like 4 (ANGPTL4) as a target gene of GPER. Treatment of trophoblast cells with G1 or 17β-estradiol (E2) activated Yes-associated protein (YAP), the major downstream effector of the Hippo pathway, via GPER but in a mammalian STE20-like protein kinase 1 (MST1)-independent manner. Using pharmacological inhibitors as well as loss- and gain-of-function approaches, our results revealed that YAP activation was required for GPER-stimulated ANGPTL4 expression. Transwell invasion assays demonstrated that activation of GPER-induced ANGPTL4 promoted cell invasion. In addition, the expression levels of GPER, YAP, and ANGPTL4 were downregulated in the placenta of patients with PE. Our findings reveal a mechanism by which GPER exerts its stimulatory effect on human trophoblast cell invasion by upregulating YAP-mediated ANGPTL4 expression.

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G Protein-Coupled Estrogen Receptor 1 (GPER1) Mediates Aldosterone-Induced Endothelial Inflammation in a Mineralocorticoid Receptor-Independent Manner

International Journal of Endocrinology ◽

10.1155/2021/5575927 ◽

2021 ◽

Vol 2021 ◽

pp. 1-8

Author(s):

Ziwei Tang ◽

Qifu Li ◽

Qingfeng Cheng ◽

Mei Mei ◽

Ying Song ◽

...

Keyword(s):

Endothelial Cells ◽

Estrogen Receptor ◽

Inflammatory Response ◽

G Protein ◽

Mineralocorticoid Receptor ◽

Umbilical Vein ◽

Vascular Inflammation ◽

Independent Manner ◽

G Protein Coupled ◽

Estrogen Receptor 1

Objective. It has been increasingly appreciated that G protein-coupled estrogen receptor 1 (GPER1) mediates both proinflammatory and anti-inflammatory response of estrogen. It is also involved in some rapid vascular effects of aldosterone in a mineralocorticoid receptor (MR) independent manner. However, whether GPER1 mediates aldosterone-induced inflammation response in endothelial cells and its relationship with MR are yet undetermined and therefore require further explanation. Method. Based on the hypothesis that GPER1 plays a role in the aldosterone-related vascular inflammation, the present study utilized a model of human umbilical vein endothelial cells transfected with MR siRNA and induced for inflammatory response with increasing concentration of aldosterone. Results. It was discovered that induction of aldosterone had no effect on the expression of GPER1 but promoted the expression of MR. Suppression of MR did not influence GPER1 expression, and GPER1 was capable of mediating part of aldosterone-induced endothelial inflammatory response. This effect may involve phosphoinositide 3-kinases (PI3K) pathway signaling. Conclusion. These findings not only demonstrated the role of GPER1 in aldosterone-induced vascular inflammation but also suggested an alternative for pharmaceutical treatment of hyperaldosteronism considering the unsatisfying effect on cardiovascular risks with MR antagonists.

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Activation of G Protein-Coupled Estrogen Receptor 1 Ameliorates Proximal Tubular Injury and Proteinuria in Dahl Salt-Sensitive Female Rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00267.2020 ◽

2021 ◽

Author(s):

Eman Y Gohar ◽

Rawan N Almutlaq ◽

Elizabeth M. Daugherty ◽

Maryam K. Butt ◽

Chunhua Jin ◽

...

Keyword(s):

Blood Pressure ◽

Estrogen Receptor ◽

Proximal Tubule ◽

G Protein ◽

Brush Border ◽

Kidney Injury ◽

Female Rats ◽

Independent Manner ◽

G Protein Coupled ◽

Estrogen Receptor 1

Recent evidence indicates a crucial role for G protein-coupled estrogen receptor 1 (GPER1) in the maintenance of cardiovascular and kidney health in females. The current study tested whether GPER1 activation ameliorates hypertension and kidney damage in female Dahl salt-sensitive (SS) rats fed a high-salt (HS) diet. Adult female rats were implanted with telemetry transmitters for monitoring blood pressure and osmotic minipumps releasing G1 (selective GPER1 agonist, 400 μg/kg/day, intraperitoneal) or vehicle. Two weeks after pump implantation, rats were shifted from a normal salt diet (NS, 0.4% NaCl) to a matched HS diet (4.0% NaCl) for 2 weeks. 24-hour urine samples were collected during both diet periods and urinary markers of kidney injury were assessed. Histological assessment of kidney injury was conducted after the 2-week HS diet period. Compared with values during the NS diet, 24-hour mean arterial pressure markedly increased in response to HS, reaching similar values in vehicle-treated and G1-treated rats. HS also significantly increased urinary excretion of protein, albumin, nephrin (podocyte damage marker) and KIM-1 (proximal tubule injury marker) in vehicle-treated rats. Importantly, G1 treatment prevented the HS-induced proteinuria, albuminuria and increase in KIM-1 excretion but not nephrinuria. Histological analysis revealed that HS-induced glomerular damage did not differ between groups. However, G1 treatment preserved proximal tubule brush border integrity in HS-fed rats. Collectively, our data suggest that GPER1 activation protects against HS-induced proteinuria and albuminuria in female Dahl SS rats by preserving proximal tubule brush border integrity in a blood pressure-independent manner.

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Anti-inflammatory effects of mesenchymal stem cell-derived exosomal microRNA-146a-5p and microRNA-548e-5p on human trophoblast cells

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaz054 ◽

2019 ◽

Vol 25 (11) ◽

pp. 755-771 ◽

Cited By ~ 5

Author(s):

Changwon Yang ◽

Whasun Lim ◽

Junghyun Park ◽

Sunwoo Park ◽

Seungkwon You ◽

...

Keyword(s):

Mouse Model ◽

Cell Line ◽

Trophoblast Cell ◽

Migration And Invasion ◽

Human Umbilical Cord ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Exosomal Mirnas ◽

Anti Inflammatory ◽

Human Trophoblast Cells

Abstract Human umbilical cord mesenchymal stem cells (MSCs) have been reported to improve the migration and invasion of trophoblast cells; however, little is known about whether MSC-derived exosomes and exosomal miRNAs can regulate trophoblast cell properties. In this study, we investigated whether exosomal miRNAs from amniotic fluid-derived MSC (AF-MSC) could regulate the inflammatory response of the human trophoblast cell line HTR8/SVneo. We verified the anti-inflammatory effects of AF-MSCs on lipopolysaccharide (LPS)-induced inflammatory trophoblast cells and found that miR-146a-5p and miR-548e-5p in the AF-MSC–derived exosomes regulate nuclear factor κB, AKT and mitogen-activated protein kinase protein phosphorylation. Furthermore, we found that the transfection of human trophoblast cells with miR-146a-5p and miR-548e-5p inhibitors reduced trophoblast migration (P < 0.05 vs control) and the expression of proliferating cell nuclear antigen, a protein essential for cell proliferation (P < 0.01 vs control). In particular, the miR-548e-5p inhibitor induced apoptosis, while tumor necrosis factor receptor–associated factor 6, a predicted target of miR-146a-5p and miR-548e-5p, was involved in the regulation of oxidative stress in the human trophoblast cells. In a mouse model of LPS-induced preterm birth (PB), miR-146a-5p expression was found to be relatively low in the group in which the effect of AF-MSCs was insignificant. However, this study is limited in that the changes in the expression of some genes in response to AF-MSCs differ between the cell line and mouse model. Collectively, these data show that exosomal miR-146a-5p and miR-548e-5p from AF-MSCs have anti-inflammatory effects on human trophoblast cells and may be novel targets for treating inflammatory diseases and associated problems that occur during pregnancy, such as PB.

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Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade

eLife ◽

10.7554/elife.31770 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 41

Author(s):

Christopher A Natale ◽

Jinyang Li ◽

Junqian Zhang ◽

Ankit Dahal ◽

Tzvete Dentchev ◽

...

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Immune Checkpoint ◽

Melanoma Cells ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Stem Cell Marker ◽

Estrogen Signaling ◽

Immune Memory ◽

G Protein Coupled

Female sex and history of prior pregnancies are associated with favorable melanoma outcomes. Here, we show that much of the melanoma protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on melanocytes. Selective GPER activation in primary melanocytes and melanoma cells induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemically delivered GPER agonist was well tolerated, and cooperated with immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against tumor rechallenge. GPER may be a useful, pharmacologically accessible target for melanoma.

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Estrogen Signaling through the G Protein–Coupled Estrogen Receptor Regulates Granulocyte Activation in Fish

The Journal of Immunology ◽

10.4049/jimmunol.1301613 ◽

2013 ◽

Vol 191 (9) ◽

pp. 4628-4639 ◽

Cited By ~ 49

Author(s):

Isabel Cabas ◽

M. Carmen Rodenas ◽

Emilia Abellán ◽

José Meseguer ◽

Victoriano Mulero ◽

...

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Estrogen Signaling ◽

G Protein Coupled

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Kisspeptin Regulation of Genes Involved in Cell Invasion and Angiogenesis in First Trimester Human Trophoblast Cells

PLoS ONE ◽

10.1371/journal.pone.0099680 ◽

2014 ◽

Vol 9 (6) ◽

pp. e99680 ◽

Cited By ~ 23

Author(s):

Víctor A. Francis ◽

Aron B. Abera ◽

Mushi Matjila ◽

Robert P. Millar ◽

Arieh A. Katz

Keyword(s):

Cell Invasion ◽

First Trimester ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Human Trophoblast Cells

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Pharmacologic activation of the G protein-coupled estrogen receptor inhibits pancreatic ductal adenocarcinoma

10.1101/365668 ◽

2018 ◽

Author(s):

Christopher A. Natale ◽

Jinyang Li ◽

Tzvete Dentchev ◽

Brian C. Capell ◽

John T. Seykora ◽

...

Keyword(s):

Estrogen Receptor ◽

Pancreatic Ductal Adenocarcinoma ◽

G Protein ◽

Immune Therapy ◽

Estrogen Signaling ◽

Ductal Adenocarcinoma ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Cancer Types ◽

G Protein Coupled

AbstractFemale sex is associated with lower incidence and improved clinical outcomes for many cancer types, including pancreatic ductal adenocarcinoma (PDAC). Although the mechanisms responsible for this sex difference are unknown, recent data suggests nonclassical estrogen signaling through the G Protein-coupled Estrogen Receptor (GPER) is likely involved. Here we used murine syngeneic tumor models and human xenografts to test whether GPER signaling inhibits pancreatic ductal adenocarcinoma (PDAC). Activation of GPER with the specific, small molecule agonist G-1 inhibited PDAC proliferation, depleted c-Myc and programmed death ligand 1 (PD-L1), and increased tumor cell immunogenicity. Systemically delivered G-1 was well tolerated in PDAC bearing mice, significantly prolonged survival, and markedly increased the efficacy of PD-1 targeted immune therapy. We detected GPER protein in a majority of spontaneous human PDAC tumors. These data, coupled with the wide tissue distribution of GPER, and our previous work showing that G-1 inhibits melanoma, suggest that GPER agonists may be useful against many different cancer types.

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EGF stimulates human trophoblast cell invasion by downregulating ID3-mediated KISS1 expression

Cell Communication and Signaling ◽

10.1186/s12964-021-00783-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Lanlan Fang ◽

Yibo Gao ◽

Zhen Wang ◽

Yuxi Li ◽

Yang Yan ◽

...

Keyword(s):

Cell Invasion ◽

Serum Levels ◽

Underlying Mechanism ◽

Clinical Results ◽

Trophoblast Cell ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Placental Disease ◽

Epidermal Growth ◽

Inhibitor Of Dna Binding

Abstract Background During pregnancy, trophoblast cell invasion needs to be finely controlled. Aberrant trophoblast cell invasion is associated with placental diseases. Epidermal growth factor (EGF) and its receptor, EGFR, are expressed in trophoblast cells. Although the pro-invasive effect of EGF on trophoblast cells has been reported, the underlying mechanism remains largely unknown. Results In the present study, we conducted an RNA sequencing (RNA-seq) to HTR-8/SVneo human trophoblast cells in response to EGF and identified KISS1 as a target gene of EGF. The human KISS1 gene encodes kisspeptin, also known as metastin, which can suppress tumor metastasis. Our results showed that EGF treatment downregulated KISS1 expression and secretion by activating the EGFR-mediated PI3K/AKT signaling pathway. In addition, the expression of inhibitor of DNA-binding protein 3 (ID3) was downregulated by EGF and that was required for the EGF-suppressed KISS1 expression. Functionally, transwell invasion assays demonstrated that EGF stimulated human trophoblast cell invasion by downregulating KISS1 expression. Preeclampsia (PE) is a placental disease characterized by insufficient trophoblast cell invasion. Our clinical results revealed that serum levels of EGF were downregulated while serum and placental levels of KISS1 were upregulated in PE patients. Conclusions This study demonstrates that downregulation of EGF can lead to poor trophoblast cell invasion by increasing KISS1 expression which subsequently contributes to the pathogenesis of PE.

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