DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE232808 | GEO | 2023/11/14
REPOSITORIES: GEO
Similar Datasets
Project description:Abnormal trophoblast function is associated with diseases such as recurrent spontaneous abortion, pre-eclampsia, and preterm birth, and endangers maternal and fetal health. However, the underlying regulatory mechanisms remain unclear. In this study, we found DOCK1 expression is decreased in the placental villi of patients with recurrent spontaneous abortion, and that its expression determined the invasive properties of extravillous trophoblasts (EVTs), highlighting a previously unknown role of DOCK1 in regulating EVT function. Furthermore, DOCK1 deficiency disturbed the ubiquitinated degradation of DUSP4, leading to its accumulation. This caused inactivation of the ERK signaling pathway, resulting in inadequate EVT migration and invasion. DOCK1 was implicated in regulating the ubiquitin levels of DUSP4, possibly by modulating the E3 ligase enzyme HUWE1. The results of our in vivo experiments confirmed that the DOCK1 inhibitor TBOPP caused miscarriage in mice by inactivating the DUSP4/ERK pathway. Collectively, our results revealed the crucial role of DOCK1 in the regulation of EVT function via the DUSP4-ERK pathway and a basis for the development of novel treatments for adverse pregnancy outcomes caused by trophoblast dysfunction.
| S-EPMC10651491 | biostudies-literature
Project description:DOCK1 insufficiency disrupts trophoblast function and pregnancy outcomes via DUSP4-ERK pathway
| PRJNA974005 | ENA
Project description:Porphyromonas gingivalis is a periodontal pathogen that is also associated with preterm low birth weight delivery. We investigated the transcriptional responses of human extravillous trophoblasts (HTR-8) to infection with P. gingivalis. Over 2000 genes were differentially regulated in HTR-8 cells by P. gingivalis. In ontology analyses of regulated genes, overpopulated biological pathways included MAP kinase signaling and cytokine production. Immunoblots confirmed over expression of the MAP kinase pathway components MEK3, p38 and Max. Furthermore, P. gingivalis infection induced phosphorylation and activation of MEK3 and p38. Increased production of IL-1β and IL-8 by HTR-8 cells was demonstrated phenotypically by ELISA of HTR-8 cell lysates and culture supernatants. Thus infection of trophoblasts by P. gingivalis can impact signal transduction pathways and modulate cytokine expression, outcomes that could disrupt the maintenance of pregnancy.
2010-11-02 | GSE19810 | GEO
Project description:Invasive extravillous trophoblasts (EVTs) of the human placenta are critically involved in successful pregnancy outcome since they remodel the uterine spiral arteries to increase blood flow and oxygen delivery to the placenta and the developing fetus. To gain more insights into their biological role different primary cell culture models are commonly utilised. However, access to early placental tissue may be limited and primary trophoblasts rapidly cease proliferation in vitro impairing genetic manipulation. Hence, trophoblastic cell lines have been widely used as surrogates to study EVT function. Although the cell lines share some molecular marker expression with their primary counterpart, it is unknown to what extent they recapture the invasive phenotype of EVT. Therefore, we here report the first thorough GeneChip analyses of SGHPL-5, HTR-8/SVneo, BeWo, JEG-3 and the novel ACH-3P trophoblast cells in comparison to previously analysed primary villous cytrophoblasts and extravillous trophoblasts. To identify EVT-specific gene expression signatures in trophoblast cell lines, we calcuted differentially expressed genes between pre-defined groups based on the distinct origins of the five trophoblast cell lines under investigation. Comparison 1 comprised EVT, HTR-8/Svneo and SGHPL-5 vs choriocarcinoma cells (ACH-3P, BeWo, JEG-3). Comparison 2 comprised EVT, ACH-3P, BeWo, JEG-3 vs extravillous trophoblast cell lines (HTR-8/SVneo, SGHPL-5).
2010-09-23 | E-GEOD-20510 | biostudies-arrayexpress
Project description:Congenital heart disease (CHD) affects nearly 1% of births annually, and CHD pregnancies carry increased risk of developing pathologies of abnormal placentation. We previously reported significant developmental impacts of disrupting Hand1, a gene associated with CHD, expression in placenta trophoblast and endothelial cells in multiple mouse models. In this study, we aimed to build upon this knowledge and characterize the mechanistic impacts of disrupting HAND1 on human placenta trophoblast and vascular endothelial cell gene expression. HAND1 gene expression was silenced in BeWo cells, a choriocarcinoma model of human cytotrophoblasts, (n = 3-9 passages) and isolated human placental microvascular endothelial cells (HPMVEC; n = 3 passages), with HAND1 siRNA for 96 h. Cells were harvested, mRNA isolated and RNA sequencing performed using the Illumina NextSeq 550 platform. Normalization and differential gene expression analyses were conducted using general linear modeling in edgeR packages. Statistical significance was determined using a log2 fold change of >1.0 or < -1.0 and unadjusted p-value ≤0.05. Panther DB was used for overrepresentation analysis, and String DB for protein association network analysis. There was downregulation of 664 genes, and upregulation of 59 genes in BeWo cells with direct HAND1 knockdown. Overrepresentation analysis identified disruption to pathways including cell differentiation, localization, and cell projection organization. In contrast, only seven genes were changed with direct HAND1 knockdown in HPMVECs. Disruption to HAND1 expression significantly alters gene expression profile in trophoblast but not endothelial cells. This data provides further evidence that future studies on genetic perturbations in CHDs should consider the extra-embryonic tissue in addition to the fetal heart.
| S-EPMC9875743 | biostudies-literature
Project description:To characterize genome-wide KDM5C traget genes in HTR-8/SVneo cells transduced with KDM5C-expression vector by CUT&Tag.
2022-12-16 | GSE200540 | GEO
Project description:RNA sequencing was applied to HTR-8/SVneo human trophoblast cells in response to G1, an agonist of GPER, to identify the target genes of GPER.
2021-09-12 | GSE183879 | GEO
Project description:Disorders of neuronal mispositioning during brain development are phenotypically heterogeneous and their genetic causes remain largely unknown. Here, we report biallelic variants in a Hippo signaling factor-MOB2-in a patient with one such disorder, periventricular nodular heterotopia (PH). Genetic and cellular analysis of both variants confirmed them to be loss-of-function with enhanced sensitivity to transcript degradation via nonsense mediated decay (NMD) or increased protein turnover via the proteasome. Knockdown of Mob2 within the developing mouse cortex demonstrated its role in neuronal positioning. Cilia positioning and number within migrating neurons was also impaired with comparable defects detected following a reduction in levels of an upstream modulator of Mob2 function, Dchs1, a previously identified locus associated with PH. Moreover, reduced Mob2 expression increased phosphorylation of Filamin A, an actin cross-linking protein frequently mutated in cases of this disorder. These results reveal a key role for Mob2 in correct neuronal positioning within the developing cortex and outline a new candidate locus for PH development.
| S-EPMC5857600 | biostudies-literature
Project description:Sanguinarine, a bioactive benzophenanthridine alkaloid extracted from plants of the Papaveraceae family, has shown antitumour effects in multiple cancer cells. But the therapeutic effects and regulatory mechanisms of sanguinatine in gastric cancer (GC) remain elusive. This study was aimed to investigate the correlation of dual-specificity phosphatase 4 (DUSP4) expression with clinicopathologic features and overall survival in patients with GC and explore the effects of sanguinarine on tumour growth and invasion in GC cells (SGC-7901 and HGC-27) and underlying molecular mechanisms. Immunohistochemical analysis showed that decreased DUSP4 expression was associated with the sex, tumour size, depth of invasion and distant metastasis in patients with GC. Functional experiments including CCK-8, Transwell and flow cytometry analysis indicated that sanguinarine or DUSP4 overexpression inhibited GC cell viability and invasive potential, and induced cell apoptosis and cycle arrest in S phase, but DUSP4 knockdown attenuated the antitumour activity of sanguinarine. Further observation demonstrated that sanguinarine up-regulated the expression of DUSP4 and Bcl-2-associated X protein (Bax), but down-regulated phosphorylated extracellular signal-regulated kinase (p-ERK), proliferating cell nuclear antigen (PCNA), matrix metalloproteinase 2 (MMP-2) and B-cell lymphoma 2 (Bcl-2) expression. Taken together, our findings indicate that sanguinarine inhibits growth and invasion of GC cells through regulation of the DUSP4/ERK pathway, suggesting that sanguinarine may have potential for use in GC treatment.
| S-EPMC5431127 | biostudies-literature
Project description:Placentation requires the proper regulation of extravillous trophoblast (EVT) migration and invasion into the decidua and maternal vasculature, processes which are initiated in physiologic hypoxic conditions. Abnormal EVT migration and/or invasion have been suggested to lead to pregnancy complications, such as preeclampsia. The objectives of this study are to determine how exposure to hypoxia impacts gene expression and cellular motility of first trimester trophoblasts, and to assess if expression of migration-associated genes is dysregulated in 2nd trimester chorionic villous samples (CVS) from preeclampsia pregnancies relative to CVS from healthy pregnancies. The 1st trimester trophoblast cell line, HTR8/SVneo, was used to investigate the relationship between hypoxia and Notch signaling in trophoblast migration and invasion. RNA sequencing and quantitative RT-PCR analyses show that exposure to hypoxia (2.5% O2) activates Notch signaling in HTR-8/SVneo. We demonstrate that exposure of HTR-8/SVneo to hypoxia induces expression of genes associated with cellular migration and invasion and increases HTR-8/SVneo cellular migration and invasion, whereas inhibition of gamma-secretase decreases Notch signaling and decreases HTR-8/SVneo migration and invasion. Analysis of RNA sequencing data from CVS of preeclampsia and uncomplicated pregnancies identified significant differentially expressed genes that are involved in cellular migration and invasion. Decreased expression of migration and invasion genes in CVS from preeclampsia pregnancies, may impair trophoblast migration and invasion in the 2nd trimester of pregnancy, resulting in the development of preeclampsia.
2021-08-05 | GSE155750 | GEO