The tumor suppressor gastrokine-1 is expressed in placenta and contributes to the regulation of trophoblast migration

Fahlbusch, Fabian; Ruebner, Matthias; Huebner, Hanna; Volkert, Gudrun; Zuern, Christina; Thiel, Franziska; Koch, Melissa R.; Menendez-Castro, Carlos; Wachter, David; Hartner, Andrea; Rascher, Wolfgang

doi:10.1016/j.placenta.2013.08.005

Cited by 16 publications

(18 citation statements)

References 56 publications

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“…Another important finding in the search of obesity-related effects on term placentas was the identification of several potential target molecules that could have important roles in understanding how the placenta affects fetal development and obesity-derived offspring’s future health problems. We detected dysregulation in several genes that have been shown to play a role in the function of normal placental development in humans, including AREG [ 36 ], CCL2 [ 37 ], FOSB [ 38 ], GKN1 [ 39 ], SERPINE2 [ 40 ], SLPI [ 41 ], and XIST [ 42 ]. In addition, several of the identified dysregulated genes, including CCL2 , CGB8 , FOSB , FSTL3 , HSD11B , IGFBP1 , PRL , RBP4 , and TAC3 have been implicated in adverse pregnancy outcomes such as intrauterine growth restriction [ 23 , 25 , 26 , 28 ], large for gestational age [ 24 ], and recurrent miscarriage [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Maternal Pre-Pregnancy Obesity Is Associated with Altered Placental Transcriptome

et al. 2017

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Maternal obesity has a major impact on pregnancy outcomes. There is growing evidence that maternal obesity has a negative influence on placental development and function, thereby adversely influencing offspring programming and health outcomes. However, the molecular mechanisms underlying these processes are poorly understood. We analysed ten term placenta’s whole transcriptomes in obese (n = 5) and normal weight women (n = 5), using the Affymetrix microarray platform. Analyses of expression data were carried out using non-parametric methods. Hierarchical clustering and principal component analysis showed a clear distinction in placental transcriptome between obese and normal weight women. We identified 72 differentially regulated genes, with most being down-regulated in obesity (n = 61). Functional analyses of the targets using DAVID and IPA confirm the dysregulation of previously identified processes and pathways in the placenta from obese women, including inflammation and immune responses, lipid metabolism, cancer pathways, and angiogenesis. In addition, we detected new molecular aspects of obesity-derived effects on the placenta, involving the glucocorticoid receptor signalling pathway and dysregulation of several genes including CCL2, FSTL3, IGFBP1, MMP12, PRG2, PRL, QSOX1, SERPINE2 and TAC3. Our global gene expression profiling approach demonstrates that maternal obesity creates a unique in utero environment that impairs the placental transcriptome.

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Section: Discussionmentioning

confidence: 99%

Maternal Pre-Pregnancy Obesity Is Associated with Altered Placental Transcriptome

et al. 2017

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“…This is the first report of gastrokine-2 protein expression during embryogenesis. Gastrokine-1 protein is expressed by the trophoblasts of the placenta and is thought to regulate trophoblast migration (Fahlbusch et al, 2013). The subcellular localisation of gastrokine-2 protein in the mouse YS is intriguing.…”

Section: Discussionmentioning

confidence: 99%

Gastrokine-2 is transiently expressed in the endodermal and endothelial cells of the maturing mouse yolk sac

Antas¹,

Brigden²,

Prudence³

et al. 2014

Gene Expression Patterns

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“…As a consequence, trophoblasts are often characterized to be of pseudo-malignant nature. Not surprisingly, expression patterns of tumor suppressor genes in cancer are similar to those found in placenta [ 2 , 3 ]. Recently, retinoic acid receptor responder 1 ( RARRES1 ), also known as Tazarotene-induced gene 1 ( TIG1 ), was identified as an important tumor suppressor gene [ 4 , 5 ].…”

Section: Introductionmentioning

confidence: 73%

Hypermethylation and loss of retinoic acid receptor responder 1 expression in human choriocarcinoma

Huebner

Strick

Wachter

et al. 2017

J Exp Clin Cancer Res

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BackgroundHuman placental development resembles tumorigenesis, due to the invasive and fusogenic potential of trophoblasts. However, these features are tightly controlled in trophoblasts. Disturbance of this spatial and temporal regulation is thought to contribute to the rare formation of choriocarcinomas. Promoter hypermethylation and loss of the tumor suppressor Retinoic acid receptor responder 1 (RARRES1) were shown to contribute to cancer progression. Our study investigated the epigenetic and transcriptional regulation of RARRES1 in healthy human placenta in comparison to choriocarcinoma cell lines and cases.MethodsThree choriocarcinoma cell lines (Jeg-3, JAR and BeWo) were treated with three different retinoic acid derivates (Am580, Tazarotene and all-trans retinoic acid) and 5-aza-2′-deoxycytidine. We analyzed RARRES1 promoter methylation by pyrosequencing and performed realtime-PCR quantification to determine RARRES1 expression in placental tissue and trophoblastic cell lines. Additionally, RARRES1 was stained in healthy placentas and in biopsies of choriocarcinoma cases (n = 10) as well as the first trimester trophoblast cell line Swan71 by immunofluorescence and immunohistochemistry.ResultsIn the choriocarcinoma cell lines, RARRES1 expression could not be induced by sole retinoic acid treatment. Stimulation with 5-aza-2′-deoxycytidine significantly induced RARRES1 expression, which then could be further increased with Am580, Tazarotene and all-trans retinoic acid. In comparison to healthy placenta, choriocarcinoma cell lines showed a hypermethylation of the RARRES1 promoter, which correlated with a reduced RARRES1 expression. In concordance, RARRES1 protein expression was lost in choriocarcinoma tissue. Additionally, in the trophoblastic cell line Swan71, we found a significant induction of RARRES1 expression with increased cell density, during mitosis and in syncytial knots.ConclusionsOur findings showed that RARRES1 expression is absent in choriocarcinoma due to promoter methylation. Based on our analysis, we hypothesize that RARRES1 might exert tumor suppressive functions in multiple cellular processes (e.g. cell cycle regulation, adhesion, invasion and apoptosis).Electronic supplementary materialThe online version of this article (10.1186/s13046-017-0634-x) contains supplementary material, which is available to authorized users.

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The tumor suppressor gastrokine-1 is expressed in placenta and contributes to the regulation of trophoblast migration

Cited by 16 publications

References 56 publications

Maternal Pre-Pregnancy Obesity Is Associated with Altered Placental Transcriptome

Maternal Pre-Pregnancy Obesity Is Associated with Altered Placental Transcriptome

Gastrokine-2 is transiently expressed in the endodermal and endothelial cells of the maturing mouse yolk sac

Hypermethylation and loss of retinoic acid receptor responder 1 expression in human choriocarcinoma

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