BST2 regulates interferon gamma-dependent decrease in invasion of HTR-8/SVneo cells via STAT1 and AKT signaling pathways and expression of E-cadherin.
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ABSTRACT:
SUBMITTER: Verma S
PROVIDER: S-EPMC6973314 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Trophoblast invasion is one of the critical steps during embryo implantation. IFNG secreted during pregnancy by uterine NK cells acts as a negative regulator of invasion. IFNG in a dose dependent fashion inhibits invasion of HTR-8/SVneo trophoblastic cells. It phosphorylates STAT1 both at tyr 701 and ser 727 residues. Silencing of STAT1 significantly increases invasion (?59%) of the cells. Based on NGS data, out of 207 genes, BATF2 expression was significantly increased after IFNG treatment. Silencing of BATF2 significantly increases the invasion of cells with (?53%) or without (?44%) treatment with IFNG. Expression of BATF2 and STAT1 is dependent on each other, silencing of one significantly inhibit the expression of other. Interestingly, phosphorylated JUN is also regulated by BATF2 and STAT1. Collectively, these findings showed that decrease in the invasion of HTR-8/SVneo cells after IFNG treatment is controlled by STAT1 and BATF2, which further regulates the expression of JUN.
| S-EPMC6363024 | biostudies-literature
Project description:Invasion of trophoblast cells is spatio-temporally regulated by various cytokines and growth factors. In pregnancy, complications like preeclampsia, shallow invasion of trophoblast cells and low amounts of epidermal growth factor (EGF) have been reported. In the present study, regulatory mechanisms associated with EGF-mediated invasion in HTR-8/SVneo trophoblastic cells have been delineated. Treatment of HTR-8/SVneo cells with EGF (10 ng/ml) led to eight fold increase (p < 0.05) in invasion. Increased invasion of HTR-8/SVneo cells by EGF was associated with an increase in phosphorylation of ERK½. In addition, significant phosphorylation of STAT1 (ser 727) and STAT3 (both tyr 705 and ser 727 residues) was also observed, accompanied by a decrease in total STAT1. Inhibition of ERK½ phosphorylation by U0126 (10 ?M) led to a significant decrease in EGF-mediated invasion with simultaneous decrease in the phosphorylated forms of STAT3 and STAT1. Decrease in total STAT1 was also reversed on inhibition of ERK½. Interestingly, inhibition of STAT3 by siRNA led to a significant decrease in EGF-mediated invasion of HTR-8/SVneo cells and phosphorylation of STAT1, but it did not have any effect on the activation of ERK½. On the other hand, inhibition of STAT1 by siRNA, also led to a significant decrease in the EGF-mediated invasion of HTR-8/SVneo cells, showed concomitant decrease in ERK½ phosphorylation and STAT3 phosphorylation at ser 727 residue. These results suggest cross-communication between ERK½ and JAK-STAT pathways during EGF-mediated increase in invasion of trophoblast cells; phosphorylation at ser 727 residue of both STAT3 and STAT1 appears to be critical.
| S-EPMC5444796 | biostudies-literature
Project description:Pre-eclampsia is a pregnancy-related disease that may cause maternal, neonatal and fetal morbidity and mortality and exists in 3-5% of pregnancies worldwide. The discovery of dysregulated microRNAs and their roles in placental development has provided a new avenue for elucidating the mechanism involved in this pregnancy-specific disorder. Here, the roles of human miR-181a-5p, a microRNA that is increased in both the plasma and placenta of severe pre-eclamptic patients, in invasion and migration of trophoblasts were investigated. Ectopic-expression of miR-181a-5p impaired the invasion and migration of HTR-8/SVneo cells, whereas miR-181a-5p inhibition had the opposite effects. IGF2BP2, which harbors a highly conserved miR-181a-5p-binding site within its 3'-UTR, was identified to be directly inhibited by miR-181a-5p. Moreover, siRNAs targeting IGF2BP2 imitated the effects of overexpressed miR-181a-5p on HTR-8/SVneo cell invasion and migration, whereas restoring IGF2BP2 expression by overexpressing a plasmid encoding IGF2BP2 partially reversed the studied inhibitory functions of miR-181a-5p. Thus, we demonstrated here that miR-181a-5p suppresses the invasion and migration of cytotrophoblasts, and its inhibitory effects were at least partially mediated by the suppression of IGF2BP2 expression, thus shedding new light on the roles of miR-181a-5p in the pathogenesis of severe pre-eclampsia.
| S-EPMC5833820 | biostudies-other
Project description:The impaired invasion ability of trophoblast cells is related to the occurrence of preeclampsia (PE). We previously found that pregnancy-specific beta-1-glycoprotein 1 (PSG1) levels were decreased in the serum of individuals with early-onset preeclampsia (EOPE). This study investigated the effect of PSG1 on Orai1-mediated store-operated calcium entry (SOCE) and the Akt signaling pathway in human trophoblast cell migration. An enzyme-linked immunosorbent assay (ELISA) was used to determine the level of PSG1 in the serum of pregnant women with EOPE. The effects of PSG1 on trophoblast proliferation and migration were examined using cell counting kit-8 (CCK8) and wound healing experiments, respectively. The expression levels of Orai1, Akt, and phosphorylated Akt (p-Akt) were determined through Western blotting. The results confirmed that the serum PSG1 levels were lower in EOPE women than in healthy pregnant women. The PSG1 treatment upregulated the protein expression of Orai1 and p-Akt. The selective inhibitor of Orai1 (MRS1845) weakened the migration-promoting effect mediated by PSG1 via suppressing the Akt signaling pathway. Our findings revealed one of the mechanisms possibly involved in EOPE pathophysiology, which was that downregulated PSG1 may reduce the Orai1/Akt signaling pathway, thereby inhibiting trophoblast migration. PSG1 may serve as a potential target for the treatment and diagnosis of EOPE.
| S-EPMC10968057 | biostudies-literature
Project description:During chronic infection, the inflammatory cytokine interferon gamma (IFNγ) damages hematopoietic stem cells (HSCs) by disrupting quiescence and promoting excessive terminal differentiation. However, the mechanism by which IFNγ hinders HSC quiescence remains undefined. Using intravital 3-dimensional microscopy, we find that IFNγ disrupts the normally close interaction between HSCs and CXCL12-abundant reticular (CAR) cells in the HSC niche. IFNγ stimulation increases expression of the cell surface protein BST2, which we find is required for IFNγ-dependent HSC relocalization and activation. IFNγ stimulation of HSCs increases their E-selectin binding by BST2 and homing to the bone marrow, which depends on E-selectin binding. Upon chronic infection, HSCs from mice lacking BST2 are more quiescent and more resistant to depletion than HSCs from wild-type mice. Overall, this study defines a critical mechanism by which IFNγ promotes niche relocalization and activation in response to inflammatory stimulation and identifies BST2 as a key regulator of HSC quiescence. VIDEO ABSTRACT.
| S-EPMC7816211 | biostudies-literature
Project description:Preeclampsia is a pregnancy disorder that is primarily associated with maternal and neonatal or fetal morbidity and mortality. The discovery of dysregulated microRNAs (miRs) and their roles in preeclampsia has provided new insight into the mechanisms involved in pregnancy‑related disorders. In the present study, quantitative PCR demonstrated that the expression levels of miR‑524‑5p were lower in patients with preeclampsia than those in normal pregnant women. Cell Counting Kit‑8 and Transwell assays indicated that overexpression of miR‑524‑5p promoted the proliferation and invasion of HTR‑8/SVneo cells, whereas inhibition of miR‑524‑5p suppressed HTR‑8/SVneo cell proliferation and invasion. Furthermore, NUMB endocytic adaptor protein (NUMB), a negative regulator of the Notch signaling pathway and a target gene of miR‑524‑5p, limited the effects of miR‑524‑5p on HTR‑8/SVneo cell invasion and migration. The present study demonstrated that miR‑524‑5p regulated the proliferation and invasion of HTR‑8/SVneo cells at least partly by targeting NUMB to regulate the Notch signaling pathway.
| S-EPMC8060792 | biostudies-literature
Project description:Hepatocyte growth factor (HGF) is reported to be down-regulated in pregnancy complications like intrauterine growth retardation and preeclampsia, which are associated with abnormal trophoblast migration/invasion. In this study, role of HGF and associated signaling pathways has been investigated in HTR-8/SVneo trophoblastic cells migration/invasion under normoxia (20% O2) and hypoxia (2% O2). HTR-8/SVneo cells exposed to hypoxia showed increase in migration and invasion as compared to cells incubated under normoxic conditions. The migration/invasion under both normoxic and hypoxic conditions was further enhanced after treatment with HGF. Subsequent to treatment with HGF, a significant increase in expression of MMP2 & MMP3 under normoxia and MMP1 & MMP9 under hypoxia was observed. Treatment of HTR-8/SVneo cells with HGF under hypoxia also led to decrease in TIMP1. Treatment of the cells with HGF led to activation of mitogen activated protein kinases (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. Inhibition of MAPK by U0126 and PI3K by LY294002 led to concomitant decrease in the HGF-mediated migration/invasion of HTR-8/SVneo cells. HGF treatment under hypoxia also led to a significant increase in hypoxia inducible factor (HIF-1α) expression. Additionally, inhibition of HIF-1α by siRNA led to decrease in HGF-mediated migration of HTR-8/SVneo cells under hypoxic conditions. Inhibition of HGF activated MAPK and PI3K signaling led to reduction in HIF-1α expression under hypoxia. In conclusion, HGF facilitates HTR-8/SVneo cell migration/invasion by activation of MAPK/PI3K signaling pathways and increased expression of MMPs. HIF-1α has a role in HGF-mediated increase in migration under hypoxic conditions.
| S-EPMC6946778 | biostudies-literature
Project description:The proliferation of extravillous trophoblasts (EVT) and their further migration, invasion, and differentiation into the decidual and myometrial vasculature are vital for spiral artery remodeling. These physiological functions of EVT are also essential steps in the implantation of the human embryo and the formation of the placenta and are closely related to pregnancy maintenance and the occurrence of abortion. Hyperin is a flavonoid with anti-inflammatory, pro-proliferative, and anti-apoptotic properties. Consequently, we investigated the previously unexplored effects of hyperin on the proliferation, migration, and invasion of HTR-8/SVneo cells. Human extravillous trophoblast-derived HTR-8/SVneo cells were incubated with different concentrations of hyperin (0, 5, 10, 25, 50, and 100 μM) to observe the changes in cell proliferation, migration, invasive capacity, and pathway activation. Proliferation, migration, and invasion were promoted by activating the JAK1/STAT3 pathway in HTR-8/SVneo cells treated with hyperin. In addition, brepocitinib (PF-06700841) significantly inhibited the proliferation, migration, and invasion effects of hyperin on HTR-8/SVneo cells. In vivo experiments confirmed that hyperin reduces the embryo loss rate in recurrent spontaneous abortion (RSA) model mice. Furthermore, our study revealed that hyperin promoted the proliferation, migration, and invasion of HTR-8/SVneo cells via activation of the JAK1/STAT3 pathway, further improving pregnancy outcomes in RSA.
| S-EPMC9898646 | biostudies-literature
Project description:BackgroundValproate, thalidomide and alcohol (ethanol) exposure during the first trimester of pregnancy is known to cause several developmental disorders. All these teratogens are known to pass the placental barrier and interfere directly with the normal development of the fetus. However, these teratogens also alter the formation and function of the placenta itself which may in turn affect the proper nourishment and development of the fetus. Optimum development of the placenta requires adequate invasion of trophoblast into the maternal uterine tissues. Changes in the migratory behavior of trophoblast by maternal exposure to these teratogens during placentogenesis may therefore alter the structure and function of the placenta.MethodsIn the present study, the effects of sodium valproate, thalidomide and alcohol on the migration of human first trimester trophoblast cell line (HTR-8/SVneo) were examined in vitro. Cells were cultured in the wells of 48-well culture plates as mono or multilayers. Circular patches of cells were removed from the center of the wells by suction, and the migration of cells into the wound was studied using microscopy. Effects of low and high concentrations of valproate, thalidomide and alcohol were examined on the healing of wounds and on the migration rate of cells by determining the wound areas at 0, 3, 6, 12, 24 and 48 h. Effects of drugs and alcohol on the proliferation and the expression levels of integrin subunits beta1 and alpha5 in cells were examined.ResultsThe migration rates of trophoblast differed between wounds created in mono and multilayers of cells. Exposure to teratogens altered the migration of trophoblast into mono and multilayer wounds. The effects of valproate, thalidomide and alcohol on the proliferation of cells during the rapid migratory phase were mild. Drug exposure caused significant changes in the expression levels of beta1 and alpha5 integrin subunits.ConclusionResults suggest that exposure to valproate, thalidomide or alcohol during the first trimester of pregnancy may change the ultrastructure of the placenta by altering the migration of trophoblast cells and this effect may be mediated by drug- or alcohol-induced changes in the expression levels of beta1 and alpha5 integrin subunits.
| S-EPMC1592099 | biostudies-literature
Project description:Recurrent spontaneous abortion (RSA) is a kind of pathological pregnancy, and abnormal function of trophoblast cells may be related to a variety of pregnancy complications including RSA. Psoralen is an effective ingredient extracted from Cullen corylifolium (L.) Medik. with multiple bioactivities mainly including anti-osteoporotic, anti-tumor, anti-inflammatory, and estrogen-like effects. However, the exact role of psoralen on trophoblast invasiveness has not been investigated thus far. In the present study, the effects of psoralen on the proliferation, migration, and invasion abilities of HTR-8/SVneo cells were evaluated by the CCK-8 and Transwell assays. The expression patterns of nuclear factor κB (NF-κB)/p65 and metalloproteinases (MMP)-2 and MMP-9 were characterized by further experiments including real-time quantitative polymerase chain reaction and Western blot. Indirect immunofluorescence was applied to track the NF-κB p65 translocation. Herein, we found that cell viability and invasive ability were promoted by psoralen in a concentration-dependent manner. Psoralen concentration-dependently enhanced both MMP-2 and MMP-9 expression and their activity of HTR-8/SVneo cells. Additionally, we observed accelerated nuclear accumulation and enhanced nuclear translocation of p65 in the presence of psoralen. Furthermore, invasiveness enhancement of psoralen on HTR-8/SVneo cells was partly eliminated by a NF-κB pathway inhibitor. Thus, our findings suggest that psoralen may serve as a potential repurpose drug candidate that can be used to induce migration and invasion of trophoblast cells through strengthening the NF-κB pathway.
| S-EPMC9024043 | biostudies-literature