Upregulated LncZBTB39 in pre-eclampsia and its effects on trophoblast invasion and migration via antagonizing the inhibition of miR-210 on THSD7A expression

Abstract Fetal growth restriction (FGR) is a condition in which a newborn fails to achieve his or her prospective hereditary growth potential. This condition is associated with high newborn mortality, second only to that associated with premature birth. FGR is associated with maternal, fetal, and placental abnormalities. Although the placenta is considered to be an important organ for supplying nutrition for fetal growth, research on FGR is limited, and treatment through the placenta remains challenging, as neither proper uterine intervention nor its pathogenesis have been fully elucidated. Yes-associated protein (YAP), as the effector of the Hippo pathway, is widely known to regulate organ growth and cancer development. Therefore, the correlation of the placenta and YAP was investigated to elucidate the pathogenic mechanism of FGR. Placental samples from humans and mice were collected for histological and biomechanical analysis. After investigating the location and role of YAP in the placenta by immunohistochemistry, we observed that YAP and cytokeratin 7 have corresponding locations in human and mouse placentas. Moreover, phosphorylated YAP (p-YAP) was upregulated in FGR and gradually increased as gestational age increased during pregnancy. Cell function experiments and mRNA-Seq demonstrated impaired YAP activity mediated by extracellular signal-regulated kinase inhibition. Established FGR-like mice also recapitulated a number of the features of human FGR. The results of this study may help to elucidate the association of FGR development with YAP and provide an intrauterine target that may be helpful in alleviating placental dysfunction.

Download Full-text

The Cytokine Gene CXCL14 Restricts Human Trophoblast Cell Invasion by Suppressing Gelatinase Activity

Endocrinology ◽

10.1210/en.2009-0570 ◽

2009 ◽

Vol 150 (12) ◽

pp. 5596-5605 ◽

Cited By ~ 20

Author(s):

HaiBin Kuang ◽

Qi Chen ◽

Ying Zhang ◽

Li Zhang ◽

HongYing Peng ◽

...

Keyword(s):

Trophoblast Cell ◽

Trophoblast Invasion ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Gelatinase Activity ◽

Invasion And Migration ◽

Human Pregnancy ◽

Decidual Cells ◽

And Migration ◽

Maternal Fetal Interface

Abstract Well-controlled trophoblast invasion into uterine decidua is a critical process for the normal development of placenta, which is tightly regulated by various factors produced within the trophoblast-endometrial microenvironment. CXCL14 is involved in tumor growth and metastasis, and its expression in placenta is temporally regulated during pregnancy. However, the role of CXCL14 in trophoblast function during human pregnancy is not clear. In this study, by using RT-PCR through human pregnancy, we found that CXCL14 was selectively expressed at early but not late pregnancy. Immunostaining revealed that CXCL14 proteins were strongly expressed in villous cytotrophoblasts and moderately in decidualized stromal cells but very weakly in syncytiotrophoblasts and extravillous trophoblasts. The effect of CXCL14 on trophoblast invasion were examined by using human villous explants cultured on Matrigel and further proved by invasion and migration assay of primary trophoblast cells and trophoblast cell line HTR-8/SVneo. Our data showed that CXCL14 significantly inhibited outgrowth of villous explant in vitro; this effect is due to suppression of trophoblast invasion and migration through regulating matrix metalloproteinases activities, whereas the trophoblast proliferation was not affected. Moreover, because a receptor for CXCL14 has not been identified, we performed further cell-specific CXCL14 binding activities with regard to different cell types within the maternal-fetal interface. Our data revealed that CXCL14 could specifically bind to trophoblast cells but not decidual cells from the maternal-fetal interface. These results suggest that CXCL14 plays an important role in regulating trophoblast invasion through an autocrine/paracrine manner during early pregnancy.

Download Full-text

Interleukin-27 Inhibits Trophoblast Cell Invasion and Migration by Affecting the Epithelial–Mesenchymal Transition in Preeclampsia

Reproductive Sciences ◽

10.1177/1933719118799206 ◽

2018 ◽

Vol 26 (7) ◽

pp. 928-938 ◽

Cited By ~ 1

Author(s):

Huisheng Ge ◽

Nanlin Yin ◽

Ting-Li Han ◽

Dongni Huang ◽

Xuehai Chen ◽

...

Keyword(s):

Epithelial Mesenchymal Transition ◽

Trophoblast Cell ◽

Trophoblast Invasion ◽

Migration And Invasion ◽

Dependent Manner ◽

Signal Transducer ◽

Mesenchymal Transition ◽

Invasion And Migration ◽

Epithelial Phenotype ◽

And Migration

Preeclampsia (PE) is a pregnancy-specific disorder representing a major cause of maternal and perinatal morbidity and mortality. Invasive and migratory phenotypes are acquired by trophoblasts through the process of epithelial–mesenchymal transition (EMT). Studies have shown that trophoblast EMT events are dysregulated in PE and play an important role in its development. Dysregulation of interleukin (IL)-27 and IL-27R (T-cell cytokine receptor (TCCR)/WSX -1) is relevant to PE. In this study, our results demonstrated that IL-27 did not significantly affect the proliferation and apoptosis of HTR -8/SVneo trophoblast cells, while it did significantly inhibit trophoblast invasion and migration. The expression of EMT-related proteins in HTR-8/SVneo cells and extravillous explants was detected after treatment with IL-27. Expression of epithelial markers was increased, and mesenchymal marker expression was reduced. Furthermore, we found that IL-27 could induce significant phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1) and Signal Transducer and Activator of Transcription 3 (STAT3) in a time-dependent manner in HTR-8/SVneo cells. Selective inhibitors of STAT1 (STAT1 siRNA) and STAT3 (STAT3 siRNA) were used to determine whether both STAT1 and STAT3 are required for IL-27-mediated inhibition of EMT. STAT1 inhibition in IL-27-treated cells attenuated the IL-27 effect, while the inhibition of STAT3 activation had no effect on the development of the epithelial phenotype. These results demonstrate that IL-27 may inhibit trophoblast cell migration and invasion by affecting the EMT process through an STAT1-dominant pathway in PE.

Download Full-text

New insights into the function of Cullin 3 in trophoblast invasion and migration

Reproduction ◽

10.1530/rep-15-0126 ◽

2015 ◽

Vol 150 (2) ◽

pp. 139-149 ◽

Cited By ~ 9

Author(s):

Qian Zhang ◽

Song Yu ◽

Xing Huang ◽

Yi Tan ◽

Cheng Zhu ◽

...

Keyword(s):

Ex Vivo ◽

Trophoblast Invasion ◽

Trophoblast Cells ◽

Human Trophoblast ◽

Invasion And Migration ◽

Cullin 3 ◽

And Migration ◽

F Box Protein ◽

Extravillous Trophoblasts

Cullin 3 (CUL3), a scaffold protein, assembles a large number of ubiquitin ligase complexes, similar to Skp1-Cullin 1-F-box protein complex. Several genetic models have shown that CUL3 is crucial for early embryonic development. Nevertheless, the role of CUL3 in human trophoblast function remains unclear. In this study, immunostaining revealed that CUL3 was strongly expressed in the villous cytotrophoblasts, the trophoblast column, and the invasive extravillous trophoblasts. Silencing CUL3 significantly inhibited the outgrowth of villous explant ex vivo and decreased invasion and migration of trophoblast HTR8/SVneo cells. Furthermore, CUL3 siRNA decreased pro-MMP9 activity and increased the levels of TIMP1 and 2. We also found that the level of CUL3 in the placental villi from pre-eclamptic patients was significantly lower as compared to that from their gestational age-matched controls. Moreover, in the lentiviral-mediated placenta-specific CUL3 knockdown mice, lack of CUL3 resulted in less invasive trophoblast cells in the maternal decidua. Taken together, these results suggest an essential role for CUL3 in the invasion and migration of trophoblast cells, and dysregulation of its expression may be associated with the onset of pre-eclampsia.

Download Full-text

Preeclampsia and ox-LDL modify the expression of autophagy markers in placenta and first trimester trophoblast cell line impairing trophoblast invasion and migration.

Placenta ◽

10.1016/j.placenta.2019.06.331 ◽

2019 ◽

Vol 83 ◽

pp. e104-e105

Author(s):

Lorena Carvajal ◽

Claudette Cantin ◽

Bárbara Fuenzalida ◽

Susana Contreras-Duarte ◽

Jaime Gutierrez ◽

...

Keyword(s):

Cell Line ◽

First Trimester ◽

Trophoblast Cell ◽

Trophoblast Invasion ◽

Invasion And Migration ◽

And Migration ◽

Trophoblast Cell Line

Download Full-text

Abnormal Circulating Maternal miRNA Expression Is Associated with a Low (<4%) Cell-Free DNA Fetal Fraction

Diagnostics ◽

10.3390/diagnostics11112108 ◽

2021 ◽

Vol 11 (11) ◽

pp. 2108

Author(s):

Graziano Santoro ◽

Cristina Lapucci ◽

Marco Giannoccaro ◽

Simona Caporilli ◽

Martina Rusin ◽

...

Keyword(s):

Mirna Expression ◽

Target Genes ◽

Trophoblast Invasion ◽

Control Group ◽

Cell Free Dna ◽

Invasion And Migration ◽

Free Dna ◽

And Migration ◽

Migration Pathways ◽

Fetal Fraction

The present pilot study investigates whether an abnormal miRNA profile in NIPT plasma samples can explain the finding of a low cell-free DNA (cfDNA) fetal fraction (cfDNAff) in euploid fetuses and non-obese women. Twelve women who underwent neoBona® NIPT with a normal fetal karyotype were studied. Six with a cfDNAff < 4% were matched with a control group with normal levels of cfDNAff > 4%. Samples were processed using the nanostring nCounter® platform with a panel of 800 miRNAs. Four of the maternal miRNAs, miR-579, miR-612, miR-3144 and miR-6721, had a significant abnormal expression in patients. A data filtering analysis showed that miR-579, miR-612, miR-3144 and miR-6721 targeted 169, 1, 48 and 136 placenta-specific genes, respectively. miR-579, miR-3144 and miR-6721 shared placenta-specific targeted genes involved in trophoblast invasion and migration pathways (IGF2R, PTCD2, SATB2, PLAC8). Moreover, the miRNA target genes encoded proteins localized in the placenta and involved in the pathogenesis of pre-eclampsia, including chorion-specific transcription factor GCMa, PRG2, Lin-28 Homolog B and IGFBP1. In conclusion, aberrant maternal miRNA expression in circulating plasma could be a source of dysregulating trophoblast invasion and migration and could represent a novel cause of a low cfDNAff in the sera of pregnant women at the time of NIPT analysis.

Download Full-text

TRIB3-Regulated Akt Signal Pathway Affects Trophoblast Invasion in the Development of Preeclampsia

American Journal of Perinatology ◽

10.1055/s-0041-1735872 ◽

2021 ◽

Author(s):

Xin Sui ◽

Lei Zhang ◽

Xu-Feng Zhang ◽

Ya Zhang

Keyword(s):

Western Blotting ◽

Serum Levels ◽

Urinary Protein ◽

Trophoblast Invasion ◽

Akt Pathway ◽

Invasion And Migration ◽

Placental Efficiency ◽

And Migration

Objective The aim of the study is to explore the mechanism of tribbles pseudokinase 3 (TRIB3)-regulated Akt pathway in the development of preeclampsia (PE). Methods TRIB3 expression in the placenta of PE patient was determined by quantitative reverse transcriptase polymerase chain reaction and western blotting. Then HTR-8/SVneo or JEG-3 cells were transfected and divided into Mock, Control siRNA, TRIB3 siRNA-1, and TRIB3 siRNA-2 groups. Cell proliferation, invasion, and migration were determined by MTT assay, Transwell assay, and wound healing test, while the expression of TRIB3 and Akt pathway was measured by western blotting. PE rats were treated with TRIB3 siRNA, and blood pressure, 24-hour urinary protein, as well as serum levels of sFlt-1 and vascular endothelial growth factor (VEGF) were measured. Results The placenta of PE patients presented with increased TRIB3 expression. In comparison with Mock group, the proliferation, invasion, and migration of HTR-8/SVneo and JEG-3 cells in TRIB3 siRNA-1 group and TRIB3 siRNA-2 group increased, with decreased TRIB3 expression but enhanced expression of p-Akt/Akt, MMP-2, and MMP-9. Rats in PE group showed increases in mean arterial pressure, SBP, 24-hour urinary protein, and serum sFlt-1 levels, but decreases in serum VEGF levels, fetal weight, and placental efficiency. Moreover, TRIB3 expression was upregulated, while p-Akt/Akt was downregulated in the placenta of rats in PE group. However, indicators above were significantly improved in rats treated with TRIB3 siRNA. Conclusion TRIB3 was upregulated in the PE placenta, while silencing TRIB3 activated the Akt signaling pathway to promote the invasion and migration of trophoblast both in vitro and in vivo and ameliorated the development of PE symptoms in the PE rat model. Key Points

Download Full-text

The effect of IL-6 on the trophoblast cell line HTR-8/SVneo

Archives of Biological Sciences ◽

10.2298/abs1003531j ◽

2010 ◽

Vol 62 (3) ◽

pp. 531-538 ◽

Cited By ~ 3

Author(s):

Milica Jovanovic ◽

Tamara Kovacevic ◽

Ivana Stefanoska ◽

Ljiljana Vicovac

Keyword(s):

Cell Line ◽

Normal Pregnancy ◽

Blastocyst Stage ◽

Uterine Wall ◽

Trophoblast Cell ◽

Trophoblast Invasion ◽

Invasion And Migration ◽

And Migration ◽

Trophoblast Cell Line

Embryonic development up to the blastocyst stage, implantation into the uterine wall and the development of the functional placenta are steps crucial for the establishment of normal pregnancy. Specific cells of the placenta, the trophoblast cells, invade the uterine stroma and spiral arteries, adapting them to pregnancy. Interleukin-6 is present in the human endometrium during the receptive phase and early pregnancy. Trophoblasts also produce IL-6, which was found to stimulate trophoblast invasion and migration in vitro. Here we show that the activity of MMP-9 may contribute to the observed increased invasion. In addition, in the HTR-8/SVneo trophoblast cell line IL-6 increases cell proliferation. .

Download Full-text

Role of placenta-specific protein 1 in trophoblast invasion and migration

Reproduction ◽

10.1530/rep-14-0052 ◽

2014 ◽

Vol 148 (4) ◽

pp. 343-352 ◽

Cited By ~ 23

Author(s):

Wen-Lin Chang ◽

Qing Yang ◽

Hui Zhang ◽

Hai-Yan Lin ◽

Zhi Zhou ◽

...

Keyword(s):

First Trimester ◽

Specific Protein ◽

Trophoblast Invasion ◽

Specific Gene ◽

Invasion And Migration ◽

Functional Studies ◽

And Migration ◽

Extravillous Trophoblasts

Placenta-specific protein 1 (PLAC1), a placenta-specific gene, is known to be involved in the development of placenta in both humans and mice. However, the precise role of PLAC1 in placental trophoblast function remains unclear. In this study, the localization of PLAC1 in human placental tissues and its physiological significance in trophoblast invasion and migration are investigated by technical studies including real-time RT-PCR, in situ hybridization, immunohistochemistry, and functional studies by utilizing cell invasion and migration assays in the trophoblast cell line HTR8/SVneo as well as the primary inducing extravillous trophoblasts (EVTs). The results show that PLAC1 is mainly detected in the trophoblast columns and syncytiotrophoblast of the first-trimester human placental villi, as well as in the EVTs that invade into the maternal decidua. Knockdown of PLAC1 by RNA interference significantly suppresses the invasion and migration of HTR8/SVneo cells and shortens the distance of the outgrowth of the induced EVTs from the cytotrophoblast column of the explants. All the above data suggests that PLAC1 plays an important role in human placental trophoblast invasion and migration.

Download Full-text

Regulation of invasive growth: similar epigenetic mechanisms underpin tumour progression and implantation in human pregnancy

Clinical Science ◽

10.1042/cs20090503 ◽

2009 ◽

Vol 118 (7) ◽

pp. 451-457 ◽

Cited By ~ 33

Author(s):

Jo K. Perry ◽

Roger J. Lins ◽

Peter E. Lobie ◽

Murray D. Mitchell

Keyword(s):

Tumour Progression ◽

Trophoblast Invasion ◽

Intercellular Adhesion Molecule ◽

Invasive Potential ◽

Dynamic Regulation ◽

Invasion And Migration ◽

Trophoblastic Cells ◽

Diagnostic Approaches ◽

And Migration ◽

Epigenetic Processes

Malignant and trophoblastic cells share the capacity to migrate and invade surrounding tissues; however, trophoblast invasion during implantation is tightly regulated, whereas that associated with tumour progression is not. It is likely that similar mechanisms underlie the dynamic regulation of cell invasion and migration in both cases, and that these are based on epigenetic processes. This hypothesis is supported by recent results demonstrating that expression of the intercellular adhesion molecule E-cadherin, deregulation of which is associated with increased cell motility and invasive potential in cancer, is under epigenetic control in trophoblast cell lines. Further elucidation of the epigenetic pathways shared by trophoblasts and malignant cells is likely to lead to the identification of common diagnostic approaches for the early identification both of cancer and pathological pregnancies involving aberrant trophoblast invasion.

Download Full-text