The non-canonical Wnt ligand, Wnt5a, is upregulated and associated with epithelial to mesenchymal transition in epithelial ovarian cancer

Ford, Caroline; Punnia-Moorthy, Gaya; Henry, Claire; Llamosas, Estelle; Nixdorf, Sheri; Olivier, Jake; Caduff, R.; Ward, Robyn L.; Heinzelmann‐Schwarz, Viola

doi:10.1016/j.ygyno.2014.06.004

Cited by 58 publications

(54 citation statements)

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“…VIM , an intermediate filament gene, and CDH11 , which encodes a component of adherens junctions, are both considered markers of mesenchymal cells that are increased during EMT [10, 19, 20, 48]. WNT5A , a secreted signaling protein involved in canonical and non-canonical WNT signaling, and FZD7 , a receptor for WNT5A and other WNT proteins, are both overexpressed in numerous cancers where they contribute to the EMT phenotype [49, 50]. ADAM19 is involved in ectodomain shedding of cadherins, a proteolytic processing event that contributes to reduced cadherin protein levels during EMT [51, 52].…”

Section: Resultsmentioning

confidence: 99%

Partial epithelial-mesenchymal transition in keloid scars: regulation of keloid keratinocyte gene expression by transforming growth factor-β1

et al. 2016

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BackgroundKeloids are an extreme form of abnormal scarring that result from a pathological fibroproliferative wound healing process. The molecular mechanisms driving keloid pathology remain incompletely understood, hindering development of targeted, effective therapies. Recent studies in our laboratory demonstrated that keloid keratinocytes exhibit adhesion abnormalities and display a transcriptional signature reminiscent of cells undergoing epithelial-mesenchymal transition (EMT), suggesting a role for EMT in keloid pathology. In the current study, we further define the EMT-like phenotype of keloid scars and investigate regulation of EMT-related genes in keloid.MethodsPrimary keratinocytes from keloid scar and normal skin were cultured in the presence or absence of transforming growth factor beta 1 (TGF-β1) +/− inhibitors of TGF-β1 and downstream signaling pathways. Gene expression was measured using quantitative polymerase chain reaction. Migration was analyzed using an in vitro wound healing assay. Proteins in keloid scar and normal skin sections were localized by immunohistochemistry. Statistical analyses utilized SigmaPlot (SyStat Software, San Jose, CA) or SAS® (SAS Institute, Cary, NC).ResultsIn keloid and normal keratinocytes, TGF-β1 regulated expression of EMT-related genes, including hyaluronan synthase 2, vimentin, cadherin-11, wingless-type MMTV integration site family, member 5A, frizzled 7, ADAM metallopeptidase domain 19, and interleukin-6. Inhibition of canonical TGF-β1 signaling in keloid keratinocytes significantly inhibited expression of these genes, and TGF-β1 stimulation of normal keratinocytes increased their expression. The inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway or the p38 mitogen-activated protein kinase pathway attenuated TGF-β1-induced expression of subsets of these genes. Migration of keloid keratinocytes, previously shown to be increased compared with normal keratinocytes, was significantly reduced by inhibition of TGF-β1 or ERK1/2 signaling. Biomarkers of EMT, including reduced E-cadherin and increased active β-catenin, were observed in keloid epidermis in vivo. However, evidence of basement membrane breakdown in keloid scar was not observed.ConclusionsThe results suggest that keloid keratinocytes exist in an EMT-like metastable state, similar to activated keratinocytes in healing wounds. The EMT-like gene expression pattern of keloid keratinocytes is regulated by canonical and non-canonical TGF-β1 signaling pathways. Therefore, interventions targeting TGF-β1-regulated EMT-like gene expression in keloid keratinocytes may serve to suppress keloid scarring.Electronic supplementary materialThe online version of this article (doi:10.1186/s41038-016-0055-7) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Partial epithelial-mesenchymal transition in keloid scars: regulation of keloid keratinocyte gene expression by transforming growth factor-β1

et al. 2016

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“…Various signaling pathways have been implicated in gonadotropin-induced proliferation, invasion, and metastasis formation in ovarian cancer, such as the RAS/RAF/ MAPK/ERK (Pilarski et al 2012, Hilliard et al 2013, Smolle et al 2013, PI3K/PTEN/AKT/mTOR (Cancer Genome Atlas Research Network 2011, Huang et al 2011, Yamamoto et al 2011, 2012, Carden et al 2012, Abe et al 2013, Dobbin & Landen 2013, and Wnt/ b-catenin signaling pathways (Bodnar et al 2014, Ford et al 2014, Qi et al 2014. Gonadotropin (FSH and LH) receptors share various downstream signaling pathways, including PI3K and MAPK, and consequently, the potential crosstalk between gonadotropins and molecular pathway signaling is of great interest in exploring targeted cancer therapies.…”

Section: Treatments Targeting Downstream Results Of Endocrine Influencesmentioning

confidence: 99%

The role of reproductive hormones in epithelial ovarian carcinogenesis

Gharwan

Bunch

Annunziata

2015

Endocrine-Related Cancer

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Epithelial ovarian cancer comprises w85% of all ovarian cancer cases. Despite acceptance regarding the influence of reproductive hormones on ovarian cancer risk and considerable advances in the understanding of epithelial ovarian carcinogenesis on a molecular level, complete understanding of the biologic processes underlying malignant transformation of ovarian surface epithelium is lacking. Various hypotheses have been proposed over the past several decades to explain the etiology of the disease. The role of reproductive hormones in epithelial ovarian carcinogenesis remains a key topic of research. Primary questions in the field of ovarian cancer biology center on its developmental cell of origin, the positive and negative effects of each class of hormones on ovarian cancer initiation and progression, and the role of the immune system in the ovarian cancer microenvironment. The development of the female reproductive tract is dictated by the hormonal milieu during embryogenesis. Intensive research efforts have revealed that ovarian cancer is a heterogenous disease that may develop from multiple extra-ovarian tissues, including both Mü llerian (fallopian tubes, endometrium) and non-Mü llerian structures (gastrointestinal tissue), contributing to its heterogeneity and distinct histologic subtypes. The mechanism underlying ovarian localization, however, remains unclear. Here, we discuss the role of reproductive hormones in influencing the immune system and tipping the balance against or in favor of developing ovarian cancer. We comment on animal models that are critical for experimentally validating existing hypotheses in key areas of endocrine research and useful for preclinical drug development. Finally, we address emerging therapeutic trends directed against ovarian cancer.

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“…Since Wnt5a-mediated ␤-catenin-independent signaling regulates epithelial-to-mesenchymal transition (EMT) of cancerous cells (54), which is partly a disorder of cell movement, we hypothesized that Wnt5a signaling could be involved in the molecular mechanisms underlying CMV-induced reduction of trophoblast motility. Indeed, CMV infection reduced Wnt5a-induced trophoblast migration (Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Zuylen

Ford

Wong

et al. 2016

J Virol

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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...

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The non-canonical Wnt ligand, Wnt5a, is upregulated and associated with epithelial to mesenchymal transition in epithelial ovarian cancer

Cited by 58 publications

References 16 publications

Partial epithelial-mesenchymal transition in keloid scars: regulation of keloid keratinocyte gene expression by transforming growth factor-β1

Partial epithelial-mesenchymal transition in keloid scars: regulation of keloid keratinocyte gene expression by transforming growth factor-β1

The role of reproductive hormones in epithelial ovarian carcinogenesis

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

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