Stanniocalcin-1 Hormone in Nonpreeclamptic and Preeclamptic Pregnancy: Clinical, Life-Style, and Genetic Modulators

Juhanson, Peeter; Rull, Kristiina; Kikas, Triin; Laivuori, Hannele; Vaas, Pille; Kajantie, Eero; Heinonen, Seppo; Laan, Maris

doi:10.1210/jc.2016-1873

Cited by 18 publications

(18 citation statements)

References 41 publications

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“…Circulating maternal IGF‐1 acts to both reduce blood pressure and stimulate fetal growth . It has also been proposed that the effects of STC‐1 on the kidney could account for the proteinuria and renal failure that can accompany preeclampsia …”

Section: Introductionmentioning

confidence: 99%

Regulation of stanniocalcin‐1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia

et al. 2020

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Naila Abid, Joan Embola and Zoe Tryfonos contributed equally to this study.Abbreviations: 8 Br-cAMP, 8-Bromo adenosine-3', 5'-cyclic monophosphate; BSA, bovine serum albumin; cAMP, adenosine-3', 5'-cyclic monophosphate; DAB, 3,3′-diaminobenzidine; DP44mT, di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone; Epac, exchange proteins directly activated by cAMP; FCS, fetal calf serum; GSK-3β, glycogen synthase kinase-3β; hCG, human chorionic gonadotrophin; HIF, hypoxia-Inducible factor; HRE, hypoxia response element; IGF, insulin-like growth factor; IGFBP4, insulin-like growth factor binding protein; mTOR, mammalian target of rapamycin; mTORC, mammalian target of rapamycin complex; NDRG-1, N-myc downstream-regulated gene 1; NHS, National Health Service; PAPP-A, pregnancy-associated plasma protein-A; PBS, phosphate-buffered saline; PBST, phosphate-buffered saline with tween; PI 3 -Kinase, phosphatidylinositol-3 kinase; PKA, protein kinase A; SGK-1, serum and glucocorticoid-induced kinase-1; STC-1, stanniocalcin-1; TBS, tris-buffered saline; TBST, tris-buffered saline with tween. AbstractStanniocalcin-1 (STC-1) is a multi-functional glycosylated peptide present in the plasma of healthy women postpartum and increased further in pregnancies complicated by preeclampsia. Although the STC-1 gene is expressed by the placenta what regulates its secretion and from which cells at the feto-maternal interface is unknown.Here, we demonstrate for the first time that the syncytiotrophoblast and cytotrophoblast are a major site of STC-1 protein expression in first trimester placental tissue. Further, in response to low oxygen, first trimester chorionic villous tissue from pregnancies at increased risk of developing preeclampsia secreted significantly more STC-1 than normal tissue under the same conditions. Using the human trophoblast cell line BeWo we have shown that low oxygen increased the secretion of STC-1 but it required co-stimulation with the Adenosine-3', 5'-cyclic monophosphate (cAMP) analogue, 8-Bromo adenosine-3', 5'-cyclic monophosphate cAMP to reach significance. Inhibition of Hypoxia inducible factor 2α (HIF-2α) and the Phosphatidylinositol-3 kinase (PI 3 -Kinase)/AKT/Serum and glucocorticoid-induced kinase-1(SGK-1) pathway resulted in significant inhibition of STC-1 secretion. As both low oxygen and cAMP are known to play a central role in placental function, their regulation of STC-1 points to a potentially important role in the maintenance of a normal healthy pregnancy and we would hypothesize that it may act to protect against prolonged placental hypoxia seen in preeclampsia. K E Y W O R D Sfirst trimester, hypoxia, placenta, stanniocalcin-1, trophoblasts

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Section: Introductionmentioning

confidence: 99%

Regulation of stanniocalcin‐1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia

et al. 2020

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“…Until recently, studies of human placental eSNPs have been restricted to reports focusing on variants modulating transcript levels of single placental genes and their effect on pregnancy outcomes. Of the few studies on placental eQTLs, one has linked variants in FKBP5 with infant neurobehavioral phenotypes (Paquette et al, 2014), and another reported an association between STC1 eSNPs and preeclampsia (Juhanson et al, 2016). The only published large-scale placental eQTL study demonstrated that the majority of placental eSNPs are located in the vicinity of the modulated genes (eGenes) (Peng et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The Effect of Genetic Variation on the Placental Transcriptome in Humans

et al. 2019

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The knowledge of genetic variants shaping human placental transcriptome is limited and they are not cataloged in the Genotype-Tissue Expression project. So far, only one whole genome analysis of placental expression quantitative trait loci (eQTLs) has been published by Peng et al. (2017) with no external independent validation. We report the second study on the landscape of placental eQTLs. The study aimed to generate a high-confidence list of placental cis -eQTLs and to investigate their potential functional implications. Analysis of cis -eQTLs (±100 kbp from the gene) utilized 40 placental RNA sequencing and respective whole genome genotyping datasets. The identified 199 placental cis -eSNPs represented 88 independent eQTL signals (FDR < 5%). The most significant placental eQTLs (FDR < 10 -5 ) modulated the expression of ribosomal protein RPL9, transcription factor ZSCAN9 and aminopeptidase ERAP2. The analysis confirmed 50 eSNP-eGenes pairs reported by Peng et al. (2017) and thus, can be claimed as robust placental eQTL signals. The study identified also 13 novel placental eGenes. Among these, ZSCAN9 is modulated by several eSNPs (experimentally validated: rs1150707) that have been also shown to affect the methylation level of genes variably escaping X-chromosomal inactivation. The identified 63 placental eGenes exhibited mostly mixed or ubiquitous expression. Functional enrichment analysis highlighted 35 Gene Ontology categories with the top ranking pathways “ruffle membrane” (FDR = 1.81 × 10 -2 ) contributing to the formation of motile cell surface and “ATPase activity, coupled” (FDR = 2.88 × 10 -2 ), critical for the membrane transport. Placental eGenes were also significantly enriched in pathways implicated in development, signaling and immune function. However, this study was not able to confirm a significant overrepresentation of genome-wide association studies top hits among the placental eSNP and eGenes, reported by Peng et al. (2017) . The identified eSNPs were further analyzed in association with newborn and pregnancy traits. In the discovery step, a suggestive association was detected between the eQTL of ALPG (rs11678251) and reduced placental, newborn’s and infant’s weight. Meta-analysis across REPROMETA, HAPPY PREGNANCY, ALSPAC cohorts ( n = 6830) did not replicate these findings. In summary, the study emphasizes the role of genetic variation in driving the transcriptome profile of the human placenta and the importance to explore further its functional implications.

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“…Recent studies found that STC1 is expressed abundantly in a variety of mammalian tissues including kidney [ 7 ], heart [ 8 ], lung [ 9 ], ovary [ 10 ], brain [ 11 ], muscular and skeletal tissues [ 12 ]. STC1 is highly conserved during evolution, and is implicated in several physiologies and pathologies, such as pregnancy [ 13 ], angiogenesis [ 14 ], inflammation and apoptosis [ 15 ]. Although most of studies have focused on the calcium-regulating functions of STC1, increasing evidence suggests that STC1 may also play a major role in carcinoma.…”

Section: Introductionmentioning

confidence: 99%

STC1 promotes cell apoptosis via NF-κB phospho-P65 Ser536 in cervical cancer cells

Jiang

Liu

et al. 2017

Oncotarget

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Stanniocalin-1 (STC1) is a secreted glycoprotein hormone and involved in various types of human malignancies. Our previous studies revealed that STC1 inhibited cell proliferation and invasion of cervical cancer cells through NF-κB P65 activation, but the mechanism is poorly understood. In our studies, we found overexpression of STC1 promoted cell apoptosis while silencing of STC1 promoted cell growth of cervical cancer. Phospho-protein profiling and Western blotting results showed the expression of NF-κB related phosphorylation sites including NF-κB P65 (Ser536), IκBα, IKKβ, PI3K, and AKT was altered in STC1-overexpressed cervical cancer cells. Moreover, PI3K inhibitor LY294002, AKT-shRNA and IκBα-shRNA could decrease the protein content of phospho-P65 (Ser536), phospho-IκBα, phospho-AKT and phospho-IKKβ while increasing the level of P65 compared to STC1 overexpression groups in cervical cancer cells. Also, PI3K inhibitor LY294002, AKT-shRNA and IκBα-shRNA elevated the percentage of apoptosis and suppressed the G1/S transition in those cells. Additionally, STC1 level was decreased in cervical cancer, especial in stage II and III. The results of immunohistochemistry for the cervical cancer microarray showed that a lower level of STC1, phospho-PI3K and P65 protein expression in tumor tissues than that in normal tissues, and a higher level of phospho-P65 protein expression in tumor tissues, which is consistent with the results of the Western blotting. These data demonstrated that STC1 can promote cell apoptosis via NF-κB phospho-P65 (Ser536) by PI3K/AKT, IκBα and IKK signaling in cervical cancer cells. Our results offer the first mechanism that explains the link between STC1 and cell apoptosis in cervical cancer.

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Stanniocalcin-1 Hormone in Nonpreeclamptic and Preeclamptic Pregnancy: Clinical, Life-Style, and Genetic Modulators

Cited by 18 publications

References 41 publications

Regulation of stanniocalcin‐1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia

Regulation of stanniocalcin‐1 secretion by BeWo cells and first trimester human placental tissue from normal pregnancies and those at increased risk of developing preeclampsia

The Effect of Genetic Variation on the Placental Transcriptome in Humans

STC1 promotes cell apoptosis via NF-κB phospho-P65 Ser536 in cervical cancer cells

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