Up-regulation of PTEN via LPS/AP-1/NF-κB pathway inhibits trophoblast invasion contributing to preeclampsia

Xue, Pingping; Fan, Wenqiang; Diao, Zongli; Li, Yujing; Kong, Chengcai; Dai, Xiuliang; Peng, Yue; Chen, Li; Wang, Huiyan; Hu, Yali; Hu, Zhibin

doi:10.1016/j.molimm.2019.12.018

Cited by 40 publications

(38 citation statements)

References 31 publications

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“…The inhibition of NF-κB is positively associated with the inhibition of vascular disease development, including PE [30]. Contrariwise, the activation of NF-κB pathway impairs the invasion of trophoblast, thus exacerbating PE [31]. Moreover, the activation of NF-κB can stimulate the release of CXCL11 in non-small cell lung cancer cells [32].…”

Section: Discussionmentioning

confidence: 99%

MiR-101-containing extracellular vesicles bind to BRD4 and enhance proliferation and migration of trophoblasts in preeclampsia

et al. 2020

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Background: Preeclampsia (PE) is a frequently occurring pregnancy disorder in the placenta, which results in various maternal and fetal complications. The current study aims to evaluate the role of extracellular vesicles (EVs)encapsulated microRNA (miR)-101 in biological processes of trophoblasts in PE and its underlying mechanism. Methods: Human umbilical cord mesenchymal stem cell (HUCMSC) and HUCMSC-derived EVs were isolated and cultured, after which EV characterization was carried out using PKH67 staining. In silico analyses were adopted to predict the downstream target genes of miR-101, and dual luciferase reporter gene assay was applied to validate the binding affinity. Furthermore, loss-and gain-of-function approaches were adopted to determine the role of miR-101 and bromodomain-containing protein 4 (BRD4) in trophoblast proliferation and invasion using EDU staining and transwell assay. In addition, a rat model of PE was established to verify the function of EV-encapsulated miR-101 in vivo. Results: Placental tissues obtained from PE patients presented with downregulated miR-101 expression and upregulated BRD4 and CXCL11 expression. EV-encapsulated miR-101 from HUCMSCs could be delivered into the trophoblast HTR-8/SVneo cells, thus enhancing proliferation and migration of trophoblasts. Mechanically, miR-101 targeted and negatively regulated BRD4 expression. BRD4 knockdown promoted the proliferation and migration of trophoblasts by suppressing NF-κB/CXCL11 axis. EV-encapsulated miR-101 from HUCMSCs also reduced blood pressure and 24 h urine protein in vivo, thereby ameliorating PE. Conclusion: In summary, EV-encapsulated miR-101 promoted proliferation and migration of placental trophoblasts through the inhibition of BRD4 expression via NF-κB/CXCL11 inactivation.

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Section: Discussionmentioning

confidence: 99%

MiR-101-containing extracellular vesicles bind to BRD4 and enhance proliferation and migration of trophoblasts in preeclampsia

et al. 2020

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“…4 PE is generally considered to be the result of the placental failure, which is categorized by the irregular remodeling of the spiral artery due to the invasion of superficial trophoblasts. 5 As delivery is the only effective way for curing the disease, treatment is mainly concentrated on the management of blood pressure and other clinical manifestations. 6 Successful isolation of mesenchymal stem cells (MSC) from the placental decidua basalis tissue of human PE was reported by Yasser S. Basmaeil et al 7 Furthermore, the exosomes emitted by MSC encompass the curative capacity to hinder apoptosis and stimulate angiogenesis in the placenta.…”

Section: Introductionmentioning

confidence: 99%

“…Different factors are considered to be risk reasons for PE such as age, renal disease, chronic hypertension, diabetes mellitus and obesity 4 . PE is generally considered to be the result of the placental failure, which is categorized by the irregular remodeling of the spiral artery due to the invasion of superficial trophoblasts 5 . As delivery is the only effective way for curing the disease, treatment is mainly concentrated on the management of blood pressure and other clinical manifestations 6 …”

Section: Introductionmentioning

confidence: 99%

Exosomal microRNA‐139‐5p from mesenchymal stem cells accelerates trophoblast cell invasion and migration by motivation of the ERK/MMP‐2 pathway via downregulation of protein tyrosine phosphatase

Liu

Wang²,

Zhang³

et al. 2020

J of Obstet and Gynaecol

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Aim: Exosomes present essential roles for intercellular interaction via extracellular pathways during systemic dysfunctions, including preeclampsia (PE). Here, we assessed the specific mechanism of mesenchymal stem cells (MSC)-originated exosomes in PE. Methods: The effects of exosomes on trophoblasts were studied by EdU, wound healing, Transwell and TUNEL assays. By microarray analysis, we found that exosomes enhanced the microRNA-139-5p (miR-139-5p) in trophoblasts, and confirmed the target gene of miR-139-5p by bioinformatics prediction and dualluciferase reporter gene assay. At the same time, ERK/MMP-2 pathway-related biomolecules were assessed through Western blot analysis. The pathway inhibitor was used for rescue experiments. Finally, the effect of exosomes on the pathology of PE rats was verified by in vivo experiments. Results: The exosomes originated from hucMSC fostered the trophoblast cell migration, invasion and proliferation and obstructed apoptosis. Moreover, miR-139-5p could be transmitted to trophoblasts through hucMSC-secreted exosomes. miR-139-5p targeted protein tyrosine phosphatase (PTEN), which regulated the ERK/MMP-2 pathway. Inhibition of the ERK/MMP-2 pathway significantly reduced the promoting effect of exosomes on trophoblasts. Treatment with exosomes significantly lowered blood pressure values and reduced 24-h proteinuria in PE rats. Conclusion: hucMSC-originated exosomes overexpressing miR-139-5p activated the ERK/MMP-2 pathway via PTEN downregulation, thus accelerating trophoblast cell invasion and migration, and blocking apoptosis. These results demonstrated that hucMSC-derived exosomes overexpressing miR-139-5p might be an innovative direction for therapeutic approaches against PE.

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“…NF-κB has been studied as an inflammatory activator in preeclampsia (34)(35)(36). However, the specific mechanism underlying the effects of NF-κB in preeclampsia has not been elucidated.…”

Section: Discussionmentioning

confidence: 99%

Fas regulates the apoptosis and migration of trophoblast cells by targeting NF‑κB

et al. 2021

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Placental trophoblast apoptosis is a major pathological feature of preeclampsia. Fas has been reported to be highly expressed in the placentas of patients with preeclampsia. However, the role and underlying mechanisms of Fas in the pathogenesis of preeclampsia have not been elucidated. In the present study, the expression of Fas in JAR human choriocarcinoma cells was overexpressed and knocked down to determine the function and possible mechanism of Fas in trophoblast cells in the progression of preeclampsia. The results of flow cytometry, Cell Counting Kit-8 and Transwell assays indicated that the overexpression of Fas promoted apoptosis, suppressed viability and impaired the migration of the human trophoblast cells. In addition, western blotting revealed that the overexpression of Fas increased the expression of nuclear factor kB (NF-kB), Bax, tumor necrosis factor α (TNF-α) and interleukin-2 (IL-2), and decreased the expression of Bcl-2 at the protein level in trophoblast cells. By contrast, the knockdown of Fas decreased the apoptosis of trophoblast cells and increased their viability and migration. In addition, the knockdown of Fas suppressed the expression of NF-κB, Bax, TNF-α and IL-2, and increased the expression of Bcl-2. Notably, the overexpression of NF-κB p65 attenuated the Fas knockdown-induced inhibition of apoptosis and acceleration of migration of the trophoblast cells. The overexpression of NF-κB in trophoblast cells also reversed the reduction in Bax expression and increase in Bcl-2 expression induced by Fas knockdown in trophoblast cells. These results indicate that Fas regulates the apoptosis and migration of trophoblast cells by targeting NF-κB, which suggests that the silencing of Fas is a promising therapeutic strategy for preeclampsia.

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Up-regulation of PTEN via LPS/AP-1/NF-κB pathway inhibits trophoblast invasion contributing to preeclampsia

Cited by 40 publications

References 31 publications

MiR-101-containing extracellular vesicles bind to BRD4 and enhance proliferation and migration of trophoblasts in preeclampsia

MiR-101-containing extracellular vesicles bind to BRD4 and enhance proliferation and migration of trophoblasts in preeclampsia

Exosomal microRNA‐139‐5p from mesenchymal stem cells accelerates trophoblast cell invasion and migration by motivation of the ERK/MMP‐2 pathway via downregulation of protein tyrosine phosphatase

Fas regulates the apoptosis and migration of trophoblast cells by targeting NF‑κB

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