CLDN1 regulates trophoblast apoptosis and proliferation in preeclampsia.
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ABSTRACT:
SUBMITTER: Zhang YC
PROVIDER: S-EPMC8111329 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRecent studies have shown that the abnormal expression of long-chain non-coding RNAs (lncRNAs) can significantly affect the biological function of trophoblast cells and lead to the occurrence of preeclampsia (PE). This study explores the expression of lncRNA LINC00922 in PE and its effect on the function of placental trophoblast cells, along with the corresponding molecular mechanism, providing a theoretical basis and molecular target for understanding the occurrence, early diagnosis, and targeted therapy of PE.MethodsFluorescence quantitative PCR was used to detect the expression of LINC00922 in 30 cases of PE tissues and normal tissues. The CCK-8 assay, clone formation experiment, and flow cytometry were used to detect the effects of LINC00922 knockdown or overexpression on the proliferation, colony formation, and cell cycle of HTR-8/SVneo placental trophoblast cells. The Transwell assay was used to detect the effects of LINC00922 knockdown or overexpression on the invasion and migration of HTR 8/SVneo cells, and western blot was used to detect the expression of cell cycle-related proteins and invasion and migration-related proteins.ResultsLINC00922 was highly expressed in PE tissues. Knockdown of LINC00922 significantly inhibited the proliferation, invasion, and migration of HTR-8/SVneo cells, along with colony formation and the ability to induce cell cycle arrest in the G0/G1 phase. However, overexpression of LINC00922 had the opposite effect. Knockdown or overexpression of LINC00922 significantly affected the expression of cell cycle-related proteins cyclin-dependent kinase 2 (CDK2), G1/S-specific cyclin-D1 (Cyclin D1), p21, proliferating cell nuclear antigen (PCNA), matrix metallopeptidase 9 (MMP-9), vimentin, and E-cadherin, but had no significant effect on the expression of matrix metallopeptidase 2 (MMP-2).ConclusionsLINC00922 was highly expressed in PE, and functional experiments showed that LINC00922 could significantly affect the proliferation and invasion abilities of placental trophoblast cells, suggesting that LINC00922 may play an important role in the occurrence, early diagnosis, and treatment of PE.
| S-EPMC8576713 | biostudies-literature
Project description:Preeclampsia is believed to be caused by impaired placentation with insufficient trophoblast invasion, leading to impaired uterine spiral artery remodeling and angiogenesis. However, the underlying molecular mechanism remains unknown. We recently carried out transcriptome profiling of placental long noncoding RNAs (lncRNAs) and identified 383 differentially expressed lncRNAs in early-onset severe preeclampsia. Here, we are reporting our identification of lncRNA INHBA-AS1 as a potential causal factor of preeclampsia and its downstream pathways that may be involved in placentation. We found that INHBA-AS1 was upregulated in patients and positively correlated with clinical severity. We systematically searched for potential INHBA-AS1-binding transcription factors and their targets in databases and found that the targets were enriched with differentially expressed genes in the placentae of patients. We further demonstrated that the lncRNA INHBA-AS1 inhibited the invasion and migration of trophoblast cells through restraining the transcription factor CENPB from binding to the promoter of TNF receptor-associated factor 1 (TRAF1). Therefore, we have identified the dysregulated pathway "INHBA-AS1-CENPB-TRAF1" as a contributor to the pathogenesis of preeclampsia through prohibiting the proliferation, invasion, and migration of trophoblasts during placentation.
| S-EPMC7585871 | biostudies-literature
Project description:BackgroundPreeclampsia (PE) is a serious complication of pregnancy, with a global incidence of about 2%-8%. It is one of the important causes of morbidity and mortality among the pregnant women and perinatal infants. Circular RNA (circRNA) has been confirmed to play an important regulatory role in PE. This study aimed to evaluate the role of hsa_circ_0008726 in the occurrence and development of PE.MethodsThe expression of hsa_circ_0008726 in PE placental tissue and blood was detected by qRT-PCR. CCK-8, wound closure, and Transwell assay were used to measure cell proliferation, migration, and invasion. Bioinformatics prediction, Western blotting, and dual-luciferase reporter gene detection were used to explore the mechanism of hsa_circ_0008726 in HTR8/SVneo cells.ResultsThe expression level of circ_0008726 in the placental tissue and blood samples of PE patients was significantly higher than that of normal controls. The overexpression of circ_0008726 can significantly inhibit the proliferation, migration, and invasion ability of HTR-8/SVneo cells. While the silence of circ_0008726 showed an opposite effect. Furthermore, hsa_circ_0008726 can modulate the expression of LHX6 by adsorbing miR-1290.ConclusionHsa_circ_000872 can regulate LHX6 by adsorbing miR-1290 to inhibit PE progression, thus establishing hsa_circ_000872 as a potential target for predicting and treating PE.
| S-EPMC9279947 | biostudies-literature
Project description:Successful human pregnancy requires extensive invasion of maternal uterine tissues by the placenta. Invasive extravillous trophoblasts derived from cytotrophoblast progenitors remodel maternal arterioles to promote blood flow to the placenta. In the pregnancy complication preeclampsia, extravillous trophoblasts invasion and vessel remodeling are frequently impaired, likely contributing to fetal underperfusion and maternal hypertension. We recently demonstrated in mouse trophoblast stem cells that hypoxia-inducible factor-2 (HIF-2)-dependent Lim domain kinase 1 (LIMK1) expression regulates invasive trophoblast differentiation by modulating the trophoblast cytoskeleton. Interestingly, in humans, LIMK1 activity promotes tumor cell invasion by modulating actin and microtubule integrity, as well as by modulating matrix metalloprotease processing. Here, we tested whether HIF-2α and LIMK1 expression patterns suggested similar roles in the human placenta. We found that LIMK1 immunoreactivity mirrored HIF-2α in the human placenta in utero and that LIMK1 activity regulated human cytotrophoblast cytoskeletal integrity, matrix metallopeptidase-9 secretion, invasion, and differentiation in vitro. Importantly, we also found that LIMK1 levels are frequently diminished in the preeclampsia setting in vivo. Our results therefore validate the use of mouse trophoblast stem cells as a discovery platform for human placentation disorders and suggest that LIMK1 activity helps promote human placental development in utero.
| S-EPMC4258498 | biostudies-literature
Project description:Human placental villi are surfaced by an outer multinucleated syncytiotrophoblast and underlying mononucleated cytotrophoblasts. Conflicting data have attributed one, or the other, of these villous trophoblast phenotypes to undergo enhanced apoptosis in complicated pregnancies, compared to term, normotensive pregnancies. We use high-resolution confocal microscopy after co-staining for E-cadherin, as a trophoblast plasma membrane marker, and for the cleavage products of cytokeratin 18 and PARP1, as markers for caspase-mediated apoptosis, to distinguish between apoptotic cytotrophoblasts and apoptosis within the syncytiotrophoblast. We test the hypothesis that increased caspase-mediated apoptosis occurs in villi of placentas derived from pregnancies complicated by preeclampsia, intrauterine growth restriction (IUGR), or both. We find significantly elevated apoptosis in villous cytotrophoblasts from women with preeclampsia and/or IUGR, compared to term, normotensive pregnancies. Apoptosis of cytotrophoblasts in villi from complicated pregnancies appears to progress similarly to what we found previously for apoptotic cytotrophoblasts in villi from in term, normotensive pregnancies. Notably, caspase-mediated apoptosis was not detectable in regions with intact syncytiotrophoblast, suggesting strong repression of apoptosis in this trophoblast phenotype in vivo. We suggest that the elevated apoptosis in cytotrophoblasts in preeclampsia contributes to the placental dysfunction characteristic of this disorder. We also propose that repression of apoptosis in the syncytiotrophoblast is important to prevent apoptosis sweeping throughout the syncytium, which would result in widespread death of this essential interface for maternal-fetal exchange.
| S-EPMC3467099 | biostudies-literature
Project description:Preeclampsia has become the world's major maternal health problem putting a huge burden on mothers, newborns and also on the health systems. The pathogenesis of preeclampsia seems to include events in very early pregnancy affecting differentiation of placental villous trophoblast. The arising changes of the cell death spectrum from apoptosis via increased autophagy and aponecrosis to necrosis in turn induce systemic inflammation of the mother.Placental tissue samples and maternal serum samples from 40 pregnant women were collected from normal pregnancy, IUGR, early-onset and late-onset preeclampsia. Immunohistochemistry for LC3B and Beclin-1 was quantified using systematic random sampling techniques. Serum levels of LDH and other markers were assessed in serum.Expression of the autophagy markers LC3B and Beclin-1 was significantly different between groups as was the LC3B/Beclin-1 ratio. Early-onset preeclampsia and IUGR had the highest autophagy protein expression levels, while normal pregnancy and late-onset preeclampsia had the highest LC3B/Beclin-1 ratio. Early-onset preeclampsia had the highest negative correlation with free LDH as cell defect marker.Autophagy plays a critical role in the cell death spectrum and cellular survival capacity of villous trophoblast. Alterations in autophagic protein expression are involved in pathological pregnancies such as preeclampsia.
| S-EPMC5673174 | biostudies-literature
Project description:Pre?eclampsia is a common complication during pregnancy, characterized by hypertension and proteinuria. The pathogenesis of pre?eclampsia is not fully understood. Studies on the maternal spiral artery have led scientists to consider that the ineffective infiltration of placental trophoblast cells may be a primary cause of pre?eclampsia. The present study aimed to investigate the differences in the profiles of long non?coding RNAs (lncRNAs) between the placentas of patients with pre?eclampsia and those of healthy pregnant women. The involvement of the differentially expressed lncRNAs in the biological activity of trophoblast cells was also assessed. A total of 26 differentially expressed lncRNAs were identified between the pre?eclampsia and healthy groups. Upregulation of NR_002794 was found in tissues from patients with pre?eclampsia. In SWAN71 trophoblast cells, NR_002794 had suppressive effects on proliferation and migration, and resulted in an increased rate of apoptosis. Furthermore, lncRNA NR_002794 had no effect on the phagocytosis of trophoblast cells. The present study suggested that abnormal levels of NR_002794 may lead to atypical conditions in trophoblast cells, which may be associated with the failure of maternal spiral artery remodeling during pregnancy and, consequently, with the development of pre?eclampsia.
| S-EPMC6797946 | biostudies-literature
Project description:ObjectivesThis study is aimed at investigating the role of PIWIL1/piRNA in the development of preeclampsia.MethodsHigh-throughput sequencing was performed in 5 preeclampsia and 5 normal placentas to get a piRNA expression profile. WGCNA network was constructed to find hub piRNAs. Through target gene prediction and protein interaction network analysis, we found the potential relationship between the key genes and PIWIL1. Subsequently, we detected the expression of PIWIL1 in 35 preeclampsia and 29 normal placental tissues. Overexpression and inhibition of PIWIL1 in HTR-8/SVneo trophoblast cells were achieved by transfecting an overexpression vector and siRNAs, respectively. Cell proliferation, apoptosis, and invasion were assessed using CCK-8, flow cytometric, and transwell assays, respectively.ResultsIt was found that a total of three piRNAs were upregulated in preeclampsia (pir-hsa-1256314, uniq_271431, and uniq_277797). And two target genes with the highest connectivity (FXR1 and DDX6) both pointed to PIWIL1. PIWIL1 expression was significantly lower in preeclampsia. In vitro studies linked PIWIL1 expression to trophoblast overgrowth. Overexpression of PIWIL1 remarkably promoted cell proliferation and invasion and inhibited apoptosis of HTR-8/SVneo cells and vice versa.ConclusionsPIWIL1/piRNA may be involved in the pathogenesis of preeclampsia by inhibiting the proliferation and invasion and promoting the apoptosis of placental trophoblasts. This study was registered with the China Clinical Trials Registry (http://www.clinicaltrials.gov): registration number ChiCTR1900027479.
| S-EPMC9023172 | biostudies-literature
Project description:Inadequate trophoblast invasion and increased trophoblast apoptosis cause serious pregnancy complications. Pleckstrin homology-like domain, family ?, member 2 (PHLDA2) has been linked to fetal size at birth and growth restriction in a number of studies. However, the impact of PHLDA2 on trophoblast function had not been studied previously, to the best of our knowledge. In the present study, immunofluorescence staining demonstrated that primary trophoblasts isolated from placental villous tissues were positive for cytokeratin 18 (CK18), vimentin and human placental lactogen (hPL). JEG-3 cells and primary trophoblasts were infected with lentivirus overexpressing PHLDA2. RT-qPCR and western blot analysis detected high levels of PHLDA2. A Cell Counting Kit-8 (CCK-8) assay showed that PHLDA2 overexpression inhibited trophoblast proliferation. In addition, PHLDA2 significantly induced apoptosis, as evidenced by Annexin V-FITC/propidium iodide (PI) and Hoechst staining, along with activation of Bax and caspase-3 and also decreased Bcl-2 expression. Further investigation showed that PHLDA2 effectively induced reactive oxygen species (ROS) generation, caused cytochrome c release from the mitochondria into the cytosol and decreased mitochondrial membrane potential. PHLDA2 likely induced apoptosis through the mitochondrial pathway. Wound healing and Transwell assays indicated that PHLDA2 overexpression efficiently suppressed cell migration and invasion. These data suggest that PHLDA2 plays an important role in the occurrence and development of pregnancy complications by promoting trophoblast apoptosis and suppressing cell invasion.
| S-EPMC4790661 | biostudies-literature
Project description:ObjectivesPreeclampsia (PE), a pregnancy-specific disorder characterized by hypertension and a variety of organ failures, currently lacks effective treatments. Urate (hydroxyiso-) hydrolase, pseudogene (URAHP), which is also a long noncoding RNA (lncRNA), has higher expression in PE placentae than in normal controls and therefore acquires an investigation for the specific mechanism of regulation.MethodsPlacentae were divided into two groups: those from patients with normal pregnancy (NP) (n = 3) and those from patients with PE (n = 3). Total RNA was extracted from the placentae and differentially expressed lncRNAs and mRNAs in PE and NP were identified by Arraystar Human LncRNA Expression Microarray V4.0 analysis. The microarray data were validated by profiling the noncoding RNA expression of URAHP in NP and PE placental tissues through quantitative real-time PCR (qRT-PCR). Then, we uncover the effect of URAHP on cell proliferation by CCK-8 assay and by 3D colony forming assay. Gene coexpression analysis was conducted to identify mRNAs coexpressed with URAHP. qRT-PCR and western blotting assays were used to measure the expression levels of URAHP and KISS1R in JAR and JET-3 cell lines.ResultsA total of 675 differentially expressed lncRNAs (DELRs) [184 upregulated DELRs and 491 downregulated DELRs] and a total of 205 differently expressed genes (DEGs) [56 upregulated mRNAs and 149 downregulated mRNAs] were finally identified between PE and NP samples through high-throughput sequencing analysis. The expression of lncRNA URAHP was increased significantly in the placentae of women with preeclampsia when compared to those with normal pregnancies. The functional assay suggested that the downregulation of URAHP alters the proliferative capacity of JAR/JET-3 cells and that the overexpression of URAHP promotes the proliferation of HTR-8/SVneo cells. We also determined that URAHP and KISS1R are coexpressed.ConclusionWe demonstrated for the first time that the pseudogene URAHP may be associated with PE. The results of this study provide a new target for the comprehensive treatment of preeclampsia.
| S-EPMC7476166 | biostudies-literature