Increased Dickkopf-1 expression in patients with unexplained recurrent spontaneous miscarriage

Bao, Shenghua; Wen, Shuai; Tong, Jing; Wang, L.; Chen, P.; Duan, Tony

doi:10.1111/cei.12066

Cited by 33 publications

(26 citation statements)

References 31 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, downregulation of the pathway could contribute to failed placentation and shallow trophoblast invasion observed in these pregnancies. Along those lines, elevated levels of Dkk1 were detected in women with recurrent abortions (Bao et al, 2013). Interestingly, cytomegalovirus (CMV) infection, a putative cause of spontaneous abortion and preterm delivery, was shown to decrease trophoblast proliferation and invasion involving inhibition of Wnt signaling.…”

Section: Wnt Signaling In Placenta and Trophoblastmentioning

confidence: 90%

Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling

Knöfler¹,

Pollheimer²

2013

Front. Genet.

252

206

View full text Add to dashboard Cite

Wingless ligands, a family of secreted proteins, are critically involved in organ development and tissue homeostasis by ensuring balanced rates of stem cell proliferation, cell death and differentiation. Wnt signaling components also play crucial roles in murine placental development controlling trophoblast lineage determination, chorioallantoic fusion and placental branching morphogenesis. However, the role of the pathway in human placentation, trophoblast development and differentiation is only partly understood. Here, we summarize our present knowledge about Wnt signaling in the human placenta and discuss its potential role in physiological and aberrant trophoblast invasion, gestational diseases and choriocarcinoma formation. Differentiation of proliferative first trimester cytotrophoblasts into invasive extravillous trophoblasts is associated with nuclear recruitment of β -catenin and induction of Wnt-dependent T-cell factor 4 suggesting that canonical Wnt signaling could be important for the formation and function of extravillous trophoblasts. Indeed, activation of the pathway was shown to promote trophoblast invasion in different in vitro trophoblast model systems as well as trophoblast cell fusion. Methylation-mediated silencing of inhibitors of Wnt signaling provided evidence for epigenetic activation of the pathway in placental tissues and choriocarcinoma cells. Similarly, abundant nuclear expression of β -catenin in invasive trophoblasts of complete hydatidiform moles suggested a role for hyper-activated Wnt signaling. In contrast, upregulation of Wnt inhibitors was noticed in placentae of women with preeclampsia, a disease characterized by shallow trophoblast invasion and incomplete spiral artery remodeling. Moreover, changes in Wnt signaling have been observed upon cytomegalovirus infection and in recurrent abortions. In summary, the current literature suggests a critical role of Wnt signaling in physiological and abnormal trophoblast function.

show abstract

Section: Wnt Signaling In Placenta and Trophoblastmentioning

confidence: 90%

Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling

Knöfler¹,

Pollheimer²

2013

Front. Genet.

252

206

View full text Add to dashboard Cite

show abstract

“…Additionally, the Wingless (Wnt) signaling pathway plays an important role in the differentiation and migration of trophoblasts (35). Abnormal expression of Wnt signaling has been reported to occur in placental tissue from clinical cases of spontaneous abortion (36) and preeclampsia (37), suggesting that aberrant Wnt signaling contributes to the pathogenesis of these diseases of pregnancy. Wnt ligands are evolutionarily conserved and couple to various receptors to activate different downstream pathways.…”

mentioning

confidence: 99%

Human Cytomegalovirus Modulates Expression of Noncanonical Wnt Receptor ROR2 To Alter Trophoblast Migration

Zuylen

Ford

Wong

et al. 2016

J Virol

View full text Add to dashboard Cite

Maternal primary cytomegalovirus (CMV) infection, reactivation, or reinfection with a different viral strain may cause fetal injury and adverse pregnancy outcomes. Increasing evidence indicates that fetal injury results not only from direct viral cytopathic damage to the CMV-infected fetus but also from indirect effects through placental infection and dysfunction. CMV alters Wingless (Wnt) signaling, an essential cellular pathway involved in placentation, as evidenced by reduced transcription of canonical Wnt target genes and decreased Wnt3a-induced trophoblast migration. Whether CMV affects the noncanonical Wnt signaling pathway has been unclear. This study demonstrates for the first time that CMV infection inhibits Wnt5a-stimulated migration of human SGHPL-4 trophoblasts and that inhibition of the pathway restores normal migration of CMV-infected cells. Western blot and real-time PCR analyses show increased expression of noncanonical Wnt receptor ROR2 in CMV-infected trophoblasts. Mimicking the CMV-induced ROR2 protein expression via ectopic expression inhibited Wnt5a-induced trophoblast migration and reduced T cell-specific factor (TCF)/lymphoid enhancer-binding factor (LEF)-mediated transcription as measured using luciferase reporter assays. Gene silencing using small interfering RNA (siRNA) duplexes decreased ROR2 transcript and protein levels. In contrast, proliferation of SGHPL-4 trophoblasts, measured by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was not affected. The siRNA-mediated downregulation of ROR2 in trophoblasts rescued CMV-induced reduction in trophoblast migration. These data suggest a mechanism where CMV alters the expression of the Wnt receptor ROR2 to alter Wnt5a-mediated signaling and inhibit trophoblast motility. Inhibition of this mechanism may be a target for therapeutic intervention for CMV-induced placental damage and consequent fetal damage in congenital CMV infections. IMPORTANCEMaternal primary cytomegalovirus (CMV) infection, reactivation, or reinfection with a different viral strain may cause fetal injury and adverse pregnancy outcomes. Increasing evidence indicates that fetal injury results not only from direct viral cytopathic damage to the CMV-infected fetus but also from indirect effects through placental infection and placental dysfunction. No effective therapy is currently proven to prevent or treat congenital CMV infection. Understanding the molecular underpinnings of CMV infection of the placenta is essential for therapeutic innovations and vaccine design. CMV alters canonical Wingless (Wnt) signaling, an essential cellular pathway involved in placental development. This study suggests a mechanism in which CMV alters the expression of noncanonical Wnt receptor ROR2 to alter motility of placental cells, which has important implications in the pathogenesis of CMV-induced placental dysfunction. Inhibition of this mechanism may be a target for therapeutic intervention for CMV-induced placental damage and consequent fetal damage in con...

show abstract

“…Accumulating data indicated that abnormal expression of Wnt/β‐catenin signaling might be associated with pathogenesis of URSA (Bao et al, ; Li et al, ). In the present study, we found that besides the decreased expression of active β‐catenin, WNT2 was also significantly reduced in villi of URSA compared to that of healthy women.…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of WNT2 in villi of unexplained recurrent spontaneous abortion patients may cause trophoblast cell dysfunction via downregulated Wnt/β‐catenin signaling pathway

Wang

et al. 2017

Cell Biology International

View full text Add to dashboard Cite

WNT2 has been reported to be important for placental development, especially for the proper vascularization of the placenta. However, its precise role in first-trimester trophoblast cells is still unknown. WNT2 expression in the villous tissues of unexplained recurrent spontaneous abortion (URSA) patients was compared with that of healthy women by Western blot. The function of WNT2 in HTR-8/SVneo trophoblast cells was evaluated by altering the cellular WNT2 level through overexpression and shRNA knockdown. The molecular mechanism of the effect of WNT2 on trophoblast cells was investigated. The association of WNT2 with the Wnt/β-catenin signaling pathway was studied through Western blot and immunofluorescence. Results showed that WNT2 protein expression was significantly decreased in villi of the URSA group compared with the control group. In vitro studies showed that WNT2 could promote human trophoblast cell proliferation and migration through activating the Wnt/β-catenin signaling pathway. Moreover, upon the knockdown of WNT2, trophoblast cell proliferation and migration were significantly suppressed. In conclusion, our study indicated that WNT2 plays an important role in trophoblast function. WNT2 insufficiency might cause impaired trophoblast cell proliferation and migration via downregulation of Wnt/β-catenin signaling pathway.

show abstract

Increased Dickkopf-1 expression in patients with unexplained recurrent spontaneous miscarriage

Cited by 33 publications

References 31 publications

Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling

Human placental trophoblast invasion and differentiation: a particular focus on Wnt signaling

Human Cytomegalovirus Modulates Expression of Noncanonical Wnt Receptor ROR2 To Alter Trophoblast Migration

Decreased expression of WNT2 in villi of unexplained recurrent spontaneous abortion patients may cause trophoblast cell dysfunction via downregulated Wnt/β‐catenin signaling pathway

Contact Info

Product

Resources

About