加载中

    First trimester maternal serum pregnancy-specific beta-1-glycoprotein (SP1) as a marker of adverse pregnancy outcome. Pihl Kasper,Larsen Torben,Laursen Inga,Krebs Lone,Christiansen Michael Prenatal diagnosis OBJECTIVE:To establish the first trimester levels of pregnancy-specific beta-1-glycoprotein (SP1) in pregnancies with adverse outcome. Furthermore, to determine the screening performance for adverse outcome using SP1 alone and in combination with other first trimester markers including proMBP and PAPP-A. METHODS:A case-control study was conducted in a primary hospital setting. The SP1 concentration was measured in first trimester maternal serum in pregnancies with small-for-gestational age fetuses (SGA) (n = 150), spontaneous preterm delivery (n = 88), preeclampsia (n = 40) and in controls (n = 500). Concentrations were converted to multiples of the median (MoM) in controls and groups were compared using Mann-Whitney U-test. Logistic regression analysis was used to determine significant factors for predicting adverse pregnancy outcome. Screening performance was assessed using receiver operating characteristic (ROC) curves. RESULTS:The SP1 MoM median was significantly reduced in cases with SGA (0.76 MoM, p < 0.0005) and spontaneous preterm delivery (0.77 MoM, p < 0.0005) whereas no alteration was found in cases with preeclampsia (0.94 MoM, p = 0.723). A significant correlation (r = 0.217) between log(10)(SP1 MoM) and the birth weight percentile was found in the SGA group. Screening performance was only slightly improved when SP1 was combined with PAPP-A or proMBP. CONCLUSION:SP1 is a first trimester maternal serum marker of SGA and preterm delivery. 10.1002/pd.2408
    Role of the pregnancy-specific glycoprotein in regulation of the cytokine and chemokine profiles of intact mononuclear cells. Rayev M B,Litvinova L S,Yurova K A,Dunets N A,Khaziakhmatova O G,Timganova V P,Bochkova M S,Khramtsov P V,Zamorina S A Doklady biological sciences : proceedings of the Academy of Sciences of the USSR, Biological sciences sections The effect of human pregnancy-specific glycoprotein (PSG) on the cytokine and chemokine production in vitro by intact mononuclear cells was studied by the method of flow fluorimetry. PSG inhibited production of the proinflammatory cytokines IL-6, IL-8, IL-17, IFN-γ, and TNF-α and chemokines CCL3/MIP-1α, CCL4/MIP-1β, CCL2/MCP-1; at the same time, PSG stimulated IL-12(p70) production. Simultaneously with increasing the VEGF level, PSG inhibited production of IL-9, IL-13, G-CSF, and GM-CSF. The PSG effect discovered can be interpreted as a contribution into the immune tolerance formation during pregnancy. 10.1134/S001249661704007X
    The role of pregnancy-specific glycoprotein 1a (PSG1a) in regulating the innate and adaptive immune response. Martinez Fernando F,Cervi Laura,Knubel Carolina P,Panzetta-Dutari Graciela M,Motran Claudia C American journal of reproductive immunology (New York, N.Y. : 1989) Among several explanations for the acceptance of the fetus, the one that suggests that the maternal immune system is suppressed or modified has been the subject of many studies. Thus, it has been proposed that the cells of innate immune system might be able to distinguish the pregnant from the non-pregnant state producing a signal, the so-called signal P. We have previously proposed that pregnancy-specific glycoprotein 1a (PSG1a), a representative member of the main glycoprotein family secreted by placental trophoblast, may modulate the activation of antigen-presenting cells promoting the T-cell shift of the maternal cell immunity toward a less harmful phenotype. In this review, we summarize current knowledge concerning the contribution of pregnancy-specific glycoprotein 1a (PSG1a) to modulate the maternal innate and adaptive immune response in order to assure a successful pregnancy. 10.1111/aji.12089
    The effect of pregnancy-specific β1-glycoprotein 1 on the transcription factor FOXP3 expression by immunocompetent cells. Zamorina S A,Litvinova L S,Yurova K A,Dunets N A,Khaziakhmatova O G,Timganova V P,Bochkova M S,Khramtsov P V,Rayev M B Doklady. Biochemistry and biophysics The role of human pregnancy-specific β1-glycoprotein (PSG) in the regulation of expression of the transcription factor FOXP3 was studied. It is found that, under conditions of directed induction of phenotypic changes in CD4 lymphocytes to regulatory T cells (Treg), PSG at high concentrations (10 and 100 μg/mL) increased FOXP3 expression. The evaluation of the spontaneous expression level of FOXP3 mRNA showed that PSG (1 and 100 μg/mL) stimulated the expression of this factor in mononuclear cells and isolated CD4 lymphocytes. Thus, PSG stimulates FOXP3 expression in immunocompetent cells. 10.1134/S1607672916050161
    Characterization of Human Pregnancy Specific Glycoprotein (PSG) Gene Copy Number Variations in Pre-eclampsia Patients. Chang Chia Lin,Chang Chia Yu,Lee Da Xian,Cheng Po Jen Advances in experimental medicine and biology Pre-eclampsia is a pregnancy-specific hypertensive disorder that affects 2-8 % of pregnancies. This disorder can lead to seizure, multi-organ failure and maternal death. The best approach to prevent pre-eclampsia-associated adverse outcomes is to be able to prevent pre-eclampsia as early as possible. Unfortunately, current diagnostic methods are ineffective at predicting the risk of pre-eclampsia during early pregnancy. In humans, low levels of a group of placenta-derived Pregnancy Specific Glycoproteins (PSGs) have been associated with intrauterine growth retardation and pre-eclampsia and there is a significant enrichment of cases with deletions in the PSG gene locus in pre-eclampsia patients. Based on these observations, we hypothesize that genomic variations at human PSG locus of maternal and/or fetal genomes may confer increased risks of pre-eclampsia. To test this hypothesis, we have recruited 90 normal control and 30 pre-eclamptic women for the analysis of fetal PSG copy number variations (CNVs).The identification of novel PSG CNV-disease relationships will provide not only a better understanding of the pathology of pre-eclampsia but also a novel opportunity to identify patients with a high risk of developing early-onset pre-eclampsia, which has a five- to tenfold higher risk of life-threatening maternal complications and fetal demise as compared to late-onset pre-eclampsia patients. 10.1007/978-3-319-42044-8_12
    Pregnancy-specific glycoproteins function as immunomodulators by inducing secretion of IL-10, IL-6 and TGF-beta1 by human monocytes. Snyder S K,Wessner D H,Wessells J L,Waterhouse R M,Wahl L M,Zimmermann W,Dveksler G S American journal of reproductive immunology (New York, N.Y. : 1989) PROBLEM:Low levels of pregnancy-specific glycoproteins (PSGs) in maternal serum have been correlated with complications of pregnancy. We investigated the ability of human PSGs to regulate in vitro production of cytokines. METHOD OF STUDY:Human monocytes and murine RAW 264.7 cells were treated with recombinant PSG1, PSG6, PSG11, or a truncated PSG6 consisting of only the N-terminal domain (PSG6N). Cytokine production in response to PSG-treatment was measured by ELISA and/or reverse transcriptase-PCR. RESULTS:All PSGs tested induced secretion of interleukin (IL)-10, IL-6 and transforming growth factor (TGF)-beta1 by both human and murine cells, but not IL-1beta, tumor necrosis factor (TNF)-alpha or IL-12. The N-terminal domain of PSG6 was sufficient for induction of monocyte cytokine secretion. Induction of IL-10 and IL-6 was preceded by an increase in the specific mRNAs. CONCLUSIONS:PSG1, PSG6, PSG6N, and PSG11 induce dose-dependent secretion of anti-inflammatory cytokines by human monocytes. Human and murine PSGs exhibit cross-species activity. Our results are consistent with a role for PSGs in modulation of the innate immune system.
    Placental specific mRNA in the maternal circulation are globally dysregulated in pregnancies complicated by fetal growth restriction. Whitehead Clare L,Walker Susan P,Ye Louie,Mendis Sonali,Kaitu'u-Lino Tu'uhevaha J,Lappas Martha,Tong Stephen The Journal of clinical endocrinology and metabolism CONTEXT:Fetal growth restriction (FGR) is a leading cause of perinatal mortality, yet no reliable screening test exists. Placental specific mRNA in the maternal circulation may reflect changes in the placental transcriptome in FGR and could be a novel biomarker for FGR. OBJECTIVE:The aim of the study was to identify placental specific RNA detectable in the maternal circulation and examine whether they are differentially expressed in severe preterm FGR. DESIGN:In silico screening was used to identify placental specific RNAs. Their expression in cases of severe FGR vs controls was examined in both maternal blood and placenta by microarray, RT-PCR, and in situ hybridization. RESULTS:Via in silico analysis, we identified 137 genes very highly expressed in the placenta relative to other tissues. Using microarray, we found that they were detectable in the maternal blood and were globally dysregulated with preterm FGR; 75 genes (55%) had a ≥1.5-fold differential expression compared to controls. Eight genes (ERVWE-1, PSG1, PLAC4, TAC3, PLAC3, CRH, CSH1, and KISS1) were validated by RT-PCR to be significantly increased in both maternal blood and placenta in a larger cohort of severe FGR compared to controls. In situ hybridization confirmed PAPPA2 and ERVWE-1 localized to the syncytiotrophoblast. CONCLUSION:There is global differential expression of placental specific mRNA in the maternal blood in pregnancies complicated by severe preterm FGR. Placental specific mRNA in maternal blood may represent a new class of biomarkers for preterm FGR. 10.1210/jc.2012-2468
    RNA sequencing identifies crucial genes in papillary thyroid carcinoma (PTC) progression. Qiu Jie,Zhang Wenwei,Xia Qingsheng,Liu Fuxue,Li Li,Zhao Shuwei,Gao Xian,Zang Chuanshan,Ge Ruifeng,Sun Yan Experimental and molecular pathology PURPOSE:The study aims to uncover molecular mechanisms of PTC (papillary thyroid carcinoma) progression and provide therapeutic biomarkers. METHODS:The paired tumor and control tissues were obtained from 5 PTC patients. RNA was extracted and cDNA libraries were constructed. RNA-sequencing (RNA-seq) was performed on the Illumina HiSeq2000 platform using paired-end method. After preprocessing of the RNA-seq data, gene expression value was calculated by RPKM. Then the differentially expressed genes (DEGs) were identified with edgeR. Functional enrichment and protein-protein interaction (PPI) network analyses were conducted for the DEGs. Module analysis of the PPI network was also performed. Transcription factors (TFs) of DEGs were predicted. RESULTS:A cohort of 496 up-regulated DEGs mainly correlating with the ECM degradation pathways, and 440 down-regulated DEGs predominantly enriching in transmembrane transport process were identified. Hub nodes in the PPI network were RRM2 and a set of collagens (COL1A1, COL3A1 and COL5A1), which were also remarkable in module 3 and module 5, respectively. Genes in module 3 were associated with cell cycle pathways, while in module 5 were related to ECM degradation pathways. PLAU, PSG1 and EGR2 were the crucial TFs with higher transcriptional activity in PTC than in control. CONCLUSION:Several genes including COL1A1, COL3A1, RRM2, PLAU, and EGR2 might be used as biomarkers of PTC therapy. Among them, COL1A1 and COL3A1 might exert their functions via involving in ECM degradation pathway, while RRM2 through cell cycle pathway. PLAU might be an active TF, whereas EGR2 might be a tumor suppressor. 10.1016/j.yexmp.2015.12.011
    Depletion of CTCF disrupts PSG gene expression in the human trophoblast cell line Swan 71. Jeong Da Som,Kim Myoung Hee,Lee Ji-Yeon FEBS open bio Pregnancy-specific glycoproteins (PSGs) are fetal proteins secreted by the placenta during pregnancy. The PSG level in maternal serum is an indicator of risk for pregnancy complications. However, little is known about the molecular mechanisms underlying PSG gene expression. Recently, the importance of epigenetic regulation of placental genes has been emphasized in the study of developmental defects and placental disease. In this study, the role of the CCCTC-binding factor (CTCF) in regulation of PSG expression was investigated to better understand the epigenetic regulatory mechanisms of the PSG genes. Inhibition of CTCF expression disturbed transcription of several PSG genes: PSG1, PSG2, PSG4, PSG5, PSG8, and PSG9 were upregulated and PSG6 and PSG11 were downregulated. These transcriptional changes were correlated with decreased CTCF binding and changes in histone modification at the PSG promoters. Our data demonstrate that CTCF is a potential mediator in the regulation of PSG gene expression. 10.1002/2211-5463.13087
    Pregnancy-specific glycoproteins bind integrin αIIbβ3 and inhibit the platelet-fibrinogen interaction. Shanley Daniel K,Kiely Patrick A,Golla Kalyan,Allen Seamus,Martin Kenneth,O'Riordan Ronan T,Ball Melanie,Aplin John D,Singer Bernhard B,Caplice Noel,Moran Niamh,Moore Tom PloS one Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members encoded by multigene families in rodents and primates. In human pregnancy, PSGs are secreted by the syncytiotrophoblast, a fetal tissue, and reach a concentration of up to 400 ug/ml in the maternal bloodstream at term. Human and mouse PSGs induce release of anti-inflammatory cytokines such as IL-10 and TGFβ1 from monocytes, macrophages, and other cell types, suggesting an immunoregulatory function. RGD tri-peptide motifs in the majority of human PSGs suggest that they may function like snake venom disintegrins, which bind integrins and inhibit interactions with ligands. We noted that human PSG1 has a KGD, rather than an RGD motif. The presence of a KGD in barbourin, a platelet integrin αIIbβ3 antagonist found in snake venom, suggested that PSG1 may be a selective αIIbβ3 ligand. Here we show that human PSG1 binds αIIbβ3 and inhibits the platelet - fibrinogen interaction. Unexpectedly, however, the KGD is not critical as multiple PSG1 domains independently bind and inhibit αIIbβ3 function. Human PSG9 and mouse Psg23 are also inhibitory suggesting conservation of this function across primate and rodent PSG families. Our results suggest that in species with haemochorial placentation, in which maternal blood is in direct contact with fetal trophoblast, the high expression level of PSGs reflects a requirement to antagonise abundant (3 mg/ml) fibrinogen in the maternal circulation, which may be necessary to prevent platelet aggregation and thrombosis in the prothrombotic maternal environment of pregnancy. 10.1371/journal.pone.0057491
    Reiterated sequences of the Streptomyces griseus plasmid pSG1. Bar-Nir D,Goedeke M E,Parag Y Plasmid pSG1 is a 16.9-kb element that is comaintained with its chromosomally integrated form in Streptomyces griseus YP5344. Three forms of amplifiable units of DNA (AUDs) were found on pSG1 in S. griseus YP5344 derivatives. All three share a 3.1-kb fragment, but each AUD is flanked by different sequences. Fragments bracketing the AUDs on pSG1 and fragments of junctions between the AUDs from amplifiable DNA sequences (ADS) containing pSG1 derivatives were cloned and sequenced. The edges of the AUDs are not homologous, nor are they flanked by direct repeats. One AUD is bracketed by a short (8-nt) inverted repeat. This AUD was reiterated in six independent isolates, suggesting preferred sites for the reiteration mechanism. Cells harboring plasmids with ADS also harbor circular molecules consisting of the same AUD. These findings suggest that reiteration is initiated by an illegitimate recombination event that yields an AUD duplication on the plasmid or an AUD DNA circle. Either of these structures may serve as an intermediate in the reiteration process. Circular AUDs may also be formed by intramolecular recombination between the repeats during the process of deamplification. 10.1006/plas.1994.1042
    iTRAQ and PRM-based quantitative proteomics in early recurrent spontaneous abortion: biomarkers discovery. Cui Ying,He Ling,Yang Chun-Yan,Ye Qian Clinical proteomics Background:Early recurrent spontaneous abortion (ERSA) is a common condition in pregnant women. To prevent ERSA is necessary to look for abortion indicators, such as hormones and proteins, in an early stage. Methods:Thirty patients with ERSA were enrolled in the case group. In the control group, we recruited 30 healthy women without a history of miscarriage undergoing voluntary pregnancy termination. The differentially expressed proteins in the serum were identified between the two groups using PRM and iTRAQ. Results:Seventy-eight differentially expressed proteins were identified. Using GO functional annotation and KEGG pathway analysis, we detected that the most significant changes occurred in the pathway of Fc gamma R-mediated phagocytosis. Meanwhile, using PRM, we identified three proteins that were closely related to abortion, B4DTF1 (highly similar to PSG1), P11464 (PSG1), and B4DF70 (highly similar to Prdx-2). The levels of B4DTF1 and P11464 were down-regulated, while the level of B4DF70 was up-regulated. Conclusions:CD45, PSG1, and Prdx-2, were significantly dysregulated in the samples of ERSA and could become important biomarkers for the prediction and diagnosis of ERSA. Larger‑scale studies are required to confirm the diagnostic value of these biomarkers. 10.1186/s12014-019-9256-y
    Pregnancy-specific glycoprotein 1 induces endothelial tubulogenesis through interaction with cell surface proteoglycans. Lisboa Felipe A,Warren James,Sulkowski Gisela,Aparicio Marta,David Guido,Zudaire Enrique,Dveksler Gabriela S The Journal of biological chemistry Pregnancy-specific β1 glycoproteins (PSGs) are the most abundant fetal proteins in the maternal bloodstream in late pregnancy. They are secreted by the syncytiotrophoblast and are detected around day 14 postfertilization. There are 11 human PSG genes, which encode a family of proteins exhibiting significant conservation at the amino acid level. We and others have proposed that PSGs have an immune modulatory function. In addition, we recently postulated that they are proangiogenic due to their ability to induce the secretion of VEGF-A and the formation of tubes by endothelial cells. The cellular receptor(s) for human PSGs remain unknown. Therefore, we conducted these studies to identify the receptor for PSG1, the highest expressed member of the family. We show that removal of cell surface glycosaminoglycans (GAGs) by enzymatic or chemical treatment of cells or competition with heparin completely inhibited binding of PSG1. In addition, PSG1 did not bind to cells lacking heparan or chondroitin sulfate on their surface, and binding was restored upon transfection with all four syndecans and glypican-1. Importantly, the presence of GAGs on the surface of endothelial cells was required for the ability of PSG1 to induce tube formation. This finding indicates that the PSG1-GAG interaction mediates at least some of the PSG1 proposed functions. 10.1074/jbc.M110.161810
    Pregnancy-specific {beta}-1-glycoprotein 1 and human leukocyte antigen-E mRNA in human sperm: differential expression in fertile and infertile men and evidence of a possible functional role during early development. Avendaño Conrado,Franchi Anahí,Jones Estella,Oehninger Sergio Human reproduction (Oxford, England) BACKGROUND:Mature spermatozoa contain thousands of mRNA transcripts. It has been recently shown that human sperm can deliver RNA into the oocyte, suggesting that mRNAs might have a role before or after fertilization. Human embryos express PSG1 (pregnancy-specific beta-1-glycoprotein 1) and HLA-E (human leukocyte antigen-E), molecules playing a role in implantation and early development. We compared PSG1 and HLA-E sperm mRNA levels in fertile and infertile men and we tested the hypothesis that these transcripts are selectively retained in the newly formed zygote. METHODS:Real-time RT-PCR was used to analyze sperm mRNA levels (n = 11 fertile, n = 31 infertile patients) of PSG1, HLA-E and PRM2 (protamine 2). The presence of PSG1 and HLA-E proteins was evaluated by western blot in sperm protein extracts (n = 3). Using ICSI of human sperm into hamster oocytes we evaluated the permanence of these mRNAs at different time points (n = 10 for each time) after fertilization. RESULTS:PSG1, HLA-E and PRM2 transcripts were demonstrated in ejaculated sperm. The fertile group showed significantly higher levels of PSG1 and HLA-E mRNA (both P < 0.05) than the infertile group, whereas PRM2 levels were not significantly different. However, PSG1 and HLA-E proteins were not found in ejaculated sperm. Following ICSI, PRM2 was undetectable after fertilization; conversely, PSG1 and HLA-E transcripts remained detectable for at least 24 h of zygotic development. CONCLUSIONS:We provide new evidence that indicates that human sperm deliver transcripts that may have a role in early embryo development and decreased levels of these transcripts may be associated with infertility. 10.1093/humrep/den381
    Activation of latent transforming growth factor-β1, a conserved function for pregnancy-specific beta 1-glycoproteins. Warren James,Im Michelle,Ballesteros Angela,Ha Cam,Moore Tom,Lambert Fanny,Lucas Sophie,Hinz Boris,Dveksler Gabriela Molecular human reproduction STUDY QUESTION:Do all 10 human pregnancy-specific beta 1-glycoproteins (PSGs) and murine PSG23 activate latent transforming growth factor-β1 (TGF-β1)? SUMMARY ANSWER:All human PSGs and murine PSG23 activated latent TGF-β1. WHAT IS KNOWN ALREADY:Two of the 10 members of the PSG1 family, PSG1 and PSG9, were previously shown to activate the soluble small latent complex of TGF-β1, a cytokine with potent immune suppressive functions. STUDY DESIGN, SIZE, DURATION:Recombinant PSGs were generated and tested for their ability to activate the small latent complex of TGF-β1 in a cell-free ELISA-based assay and in a bioassay. In addition, we tested the ability of PSG1 and PSG4 to activate latent TGF-β bound to the extracellular matrix (ECM) or on the membranes of the Jurkat human T-cell line. PARTICIPANTS/MATERIALS, SETTING, METHODS:Recombinant PSGs were generated by transient transfection and purified with a His-Trap column followed by gel filtration chromatography. The purified PSGs were compared to vehicle (PBS) used as control for their ability to activate the small latent complex of TGF-β1. The concentration of active TGF-β was measured in an ELISA using the TGF-β receptor II as capture and a bioassay using transformed mink epithelial cells that express luciferase in response to active TGF-β. The specificity of the signal was confirmed using a TGF-β receptor inhibitor. We also measured the binding kinetics of some human PSGs for the latent-associated peptide (LAP) of TGF-β using surface plasmon resonance and determined whether PSG1 and PSG4 could activate the large latent complex of TGF-β1 bound to the ECM and latent TGF-β1 bound to the cell membrane. All experiments were performed in triplicate wells and repeated three times. MAIN RESULTS AND THE ROLE OF CHANCE:All human PSGs activated the small latent complex of TGF-β1 (P < 0.05 vs. control) and showed similar affinities (KD) for LAP. Despite the lack of sequence conservation with its human counterparts, the ability to activate latent TGF-β1 was shared by a member of the murine PSG family. We found that PSG1 and PSG4 activated the latent TGF-β stored in the ECM (P < 0.01) but did not activate latent TGF-β1 bound to glycoprotein A repetitions predominant (GARP) on the surface of Jurkat T cells. LIMITATIONS, REASONS FOR CAUTION:The affinity of the interaction of LAP and PSGs was calculated using recombinant proteins, which may differ from the native proteins in their post-translational modifications. We also utilized a truncated form of murine PSG23 rather than the full-length protein. For the studies testing the ability of PSGs to activate membrane-bound TGF-β1, we utilized the T-cell line Jurkat and Jurkat cells expressing GARP rather than primary T regulatory cells. All the studies were performed in vitro. WIDER IMPLICATIONS OF THE FINDINGS:Here, we show that all human PSGs activate TGF-β1 and that this function is conserved in at least one member of the rodent PSG family. In vivo PSGs could potentially increase the availability of active TGF-β1 from the soluble and matrix-bound latent forms of the cytokine contributing to the establishment of a tolerogenic environment during pregnancy. LARGE-SCALE DATA:None. STUDY FUNDING/COMPETING INTEREST(S):The research was supported by a grant from the Collaborative Health Initiative Research Program (CHIRP). No conflicts of interests are declared by the authors. 10.1093/molehr/gay044
    Interaction of Pregnancy-Specific Glycoprotein 1 With Integrin Α5β1 Is a Modulator of Extravillous Trophoblast Functions. Rattila Shemona,Dunk Caroline E E,Im Michelle,Grichenko Olga,Zhou Yan,Yanez-Mo Maria,Blois Sandra M,Yamada Kenneth M,Erez Offer,Gomez-Lopez Nardhy,Lye Stephen J,Hinz Boris,Romero Roberto,Cohen Marie,Dveksler Gabriela Cells Human pregnancy-specific glycoproteins (PSGs) serve immunomodulatory and pro-angiogenic functions during pregnancy and are mainly expressed by syncytiotrophoblast cells. While PSG mRNA expression in extravillous trophoblasts (EVTs) was reported, the proteins were not previously detected. By immunohistochemistry and immunoblotting, we show that PSGs are expressed by invasive EVTs and co-localize with integrin 5. In addition, we determined that native and recombinant PSG1, the most highly expressed member of the family, binds to 51 and induces the formation of focal adhesion structures resulting in adhesion of primary EVTs and EVT-like cell lines under 21% oxygen and 1% oxygen conditions. Furthermore, we found that PSG1 can simultaneously bind to heparan sulfate in the extracellular matrix and to 51 on the cell membrane. Wound healing assays and single-cell movement tracking showed that immobilized PSG1 enhances EVT migration. Although PSG1 did not affect EVT invasion in the in vitro assays employed, we found that the serum PSG1 concentration is lower in African-American women diagnosed with early-onset and late-onset preeclampsia, a pregnancy pathology characterized by shallow trophoblast invasion, than in their respective healthy controls only when the fetus was a male; therefore, the reduced expression of this molecule should be considered in the context of preeclampsia as a potential therapy. 10.3390/cells8111369
    Pregnancy Specific β-1 Glycoprotein 1 is Expressed in Pancreatic Ductal Adenocarcinoma and its Subcellular Localization Correlates with Overall Survival. Shahinian Jasmin H,Fuellgraf Hannah,Tholen Stefan,Mastroianni Justin,Knopf Julia Daniela,Kuehs Markus,Mayer Bettina,Schlimpert Manuel,Kulemann Birte,Kuesters Simon,Hoeppner Jens,Wellner Ulrich F,Werner Martin,Hopt Ulrich T,Zeiser Robert,Bronsert Peter,Schilling Oliver Journal of Cancer Proteins of the pregnancy specific β-1 glycoprotein (PSG) family are renowned for their elevated expression during pregnancy. Only few reports have investigated their expression in adenocarcinomas. We studied the expression of PSG1 in pancreatic adenocarcinoma (PDAC). In a cohort of 104 patient samples, immunohistochemical analysis determined PSG1 expression in every specimen. PSG1 was found at apical and cytoplasmic localization or solely at cytoplasmic localization, with the latter case being correlated to shortened median survival (25 vs 11 months, logrank p-value < 0.001). At the same time, enzyme linked immunosorbent assay (ELISA) did not detect elevated PSG1 levels in the plasma of PDAC patients as opposed to the plasma of healthy, non-pregnant control individuals. We also probed the impact of PSG1 expression in a murine tumor model system, using subcutaneous injection of Colo-26 cells into immunocompetent BALB/c mice. Here, tumor growth was not affected by the expression of human PSG1. Our study reaffirms interest into the tumor-contextual biology of PSG proteins. 10.7150/jca.15864
    Glycan characterization of pregnancy-specific glycoprotein 1 and its identification as a novel Galectin-1 ligand. Mendoza Mirian,Lu Dongli,Ballesteros Angela,Blois Sandra M,Abernathy Kelsey,Feng Chiguang,Dimitroff Charles J,Zmuda Jonathan,Panico Maria,Dell Anne,Vasta Gerardo R,Haslam Stuart M,Dveksler Gabriela Glycobiology Pregnancy-specific beta 1 glycoprotein (PSG1) is secreted from trophoblast cells of the human placenta in increasing concentrations as pregnancy progresses, becoming one of the most abundant proteins in maternal serum in the third trimester. PSG1 has seven potential N-linked glycosylation sites across its four domains. We carried out glycomic and glycoproteomic studies to characterize the glycan composition of PSG1 purified from serum of pregnant women and identified the presence of complex N-glycans containing poly LacNAc epitopes with α2,3 sialyation at four sites. Using different techniques, we explored whether PSG1 can bind to galectin-1 (Gal-1) as these two proteins were previously shown to participate in processes required for a successful pregnancy. We confirmed that PSG1 binds to Gal-1 in a carbohydrate-dependent manner with an affinity of the interaction of 0.13 μM. In addition, we determined that out of the three N-glycosylation-carrying domains, only the N and A2 domains of recombinant PSG1 interact with Gal-1. Lastly, we observed that the interaction between PSG1 and Gal-1 protects this lectin from oxidative inactivation and that PSG1 competes the ability of Gal-1 to bind to some but not all of its glycoprotein ligands. 10.1093/glycob/cwaa034
    Recombinant Pregnancy-Specific Glycoprotein 1 Has a Protective Role in a Murine Model of Acute Graft-versus-Host Disease. Jones Karlie,Bryant Sarah,Luo Jian,Kiesler Patricia,Koontz Sherry,Warren James,Malech Harry,Kang Elizabeth,Dveksler Gabriela Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Acute graft-versus-host disease (aGVHD) is an immune-mediated reaction that can occur after hematopoietic stem cell transplantation in which donor T cells recognize the host antigens as foreign, destroying host tissues. Establishment of a tolerogenic immune environment while preserving the immune response to infectious agents is required for successful bone marrow transplantation. Pregnancy-specific glycoprotein 1 (PSG1), which is secreted by the human placenta into the maternal circulation throughout pregnancy, likely plays a role in maintaining immunotolerance to prevent rejection of the fetus by the maternal immune system. We have previously shown that PSG1 activates the latent form of transforming growth factor β1 (TGF-β), a cytokine essential for the differentiation of tolerance-inducing CD4FoxP3 regulatory T cells (Tregs). Consistent with this observation, treatment of naïve murine T cells with PSG1 resulted in a significant increase in FoxP3 cells that was blocked by a TGF-β receptor I inhibitor. We also show here that PSG1 can increase the availability of active TGF-β in vivo. As the role of CD4FoxP3 cells in the prevention of aGVHD is well established, we tested whether PSG1 has beneficial effects in a murine aGHVD transplantation model. PSG1-treated mice had reduced numbers of tissue-infiltrating inflammatory CD3 T cells and had increased expression of FoxP3 in T cells compared with vehicle-treated mice. In addition, administration of PSG1 significantly inhibited aGVHD-associated weight loss and mortality. On the other hand, administration of PSG1 was less effective in managing aGVHD in the presence of an alloimmune reaction against a malignancy in a graft-versus-leukemia experimental model. Combined, this data strongly suggests that PSG1 could be a promising treatment option for patients with aGVHD following bone marrow transplantation for a nonmalignant condition, such as an autoimmune disorder or a genetic immunodeficiency. 10.1016/j.bbmt.2018.09.022
    Comparison of serum human pregnancy-specific beta-1-glycoprotein 1 levels in pregnant women with or without preeclampsia. Temur Muzaffer,Serpim Gülçin,Tuzluoğlu Sabiha,Taşgöz Fatma Nurgül,Şahin Elif,Üstünyurt Emin Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology The aim of this study was to investigate the relationship between the maternal serum levels of pregnancy-specific beta-1-glycoprotein 1 (PSG1) and preeclampsia, and to compare levels of PSG1 in pregnancies with preeclampsia and uneventful pregnancies. A case-control study was conducted in a research and training hospital. A total of 40 women with preeclampsia and 42 healthy pregnant women who were gestational age-matched were included. Serum PSG1 levels were measured using enzyme-linked immunosorbent assay. The maternal serum PSG1 levels were significantly lower in patients with preeclampsia compared with controls (11.60 ± 8.08 vs. 17.58 ± 9.72 ng/mL,  = .003). Circulating PSG1 levels were negatively correlated with age in the preeclampsia and control groups ( = -0.322,  = .043), ( = -0.430,  = .005). PSG1 levels, age, blood urea nitrogen levels and birth weight were significantly associated with high odds of having preeclampsia. Receiver operating characteristic (ROC) curve analysis confirmed that the area under ROC curve was 0.707 (95% CI: [0.595-0.819],  < .001) for PSG1. The optimal cut-off value of PSG1 for detecting preeclampsia was ≤ 11.80 ng/mL. There may be a decrease in PSG1 production in preeclampsia-complicated pregnancies where there are pathologies related to placenta formation. A decline in PSG1 concentrations may reflect placental dysfunction.Impact Statement Previous studies have reported abnormal pregnancy-specific glycoprotein (PSG) levels in complicated pregnancies and demonstrated their importance in maintaining a healthy pregnancy. Human PSG homologues have been identified in species with haemochorial placentation such as non-human primates, rats and mice, where foetal cells are in direct contact with the maternal circulation. There are studies in which there is no clear relationship between PSGs and preeclampsia. We have demonstrated that circulating PSG1 levels were significantly lower in women with preeclampsia than in healthy pregnant women. There may be a decrease in PSG1 production in preeclampsia-complicated pregnancies where there are pathologies related to placenta formation and function. The results obtained from this current study could be used to clarify the relationship between PSG1 levels and preeclampsia. Evaluation of the role of circulating PSG1 levels in preeclampsia would be helpful in order to design further studies to determine the feasibility of using PSG1 as a serum marker to predict the risk of developing preeclampsia. The screening performance of PSG1 for preeclampsia is not yet clinically relevant, but may become so when evaluated together with other placental proteins. This will give a lead to further researches which could focus on the early detection of preeclampsia with the combination of several serum markers. 10.1080/01443615.2019.1679734
    Pro-angiogenic effects of pregnancy-specific glycoproteins in endothelial and extravillous trophoblast cells. Rattila Shemona,Kleefeldt Florian,Ballesteros Angela,Beltrame Jimena S,L Ribeiro Maria,Ergün Süleyman,Dveksler Gabriela Reproduction (Cambridge, England) We previously reported that binding to heparan sulfate (HS) is required for the ability of the placentally secreted pregnancy-specific glycoprotein 1 (PSG1) to induce endothelial tubulogenesis. PSG1 is composed of four immunoglobulin-like domains but which domains of the protein bind to HS remains unknown. To analyze the interaction of PSG1 with HS, we generated several recombinant proteins, including the individual domains, chimeric proteins between two PSG1 domains, and mutants. Using flow cytometric and surface plasmon resonance studies, we determined that the B2 domain of PSG1 binds to HS and that the positively charged amino acids encompassed between amino acids 43-59 are required for this interaction. Furthermore, we showed that the B2 domain of PSG1 is required for the increase in the formation of tubes by endothelial cells (EC) including a human endometrial EC line and two extravillous trophoblast (EVT) cell lines and for the pro-angiogenic activity of PSG1 observed in an aortic ring assay. PSG1 enhanced the migration of ECs while it increased the expression of matrix metalloproteinase-2 in EVTs, indicating that the pro-angiogenic effect of PSG1 on these two cell types may be mediated by different mechanisms. Despite differences in amino acid sequence, we observed that all human PSGs bound to HS proteoglycans and confirmed that at least two other members of the family, PSG6 and PSG9, induce tube formation. These findings contribute to a better understanding of the pro-angiogenic activity of human PSGs and strongly suggest conservation of this function among all PSG family members. 10.1530/REP-20-0169
    Expression of Pregnancy Specific β-1 Glycoprotein 1 in Cervical Cancer Cells. Rodríguez-Esquivel Miriam,Romero-Morelos Pablo,Taniguchi-Ponciano Keiko,Mendoza-Rodríguez Mónica,Marrero-Rodríguez Daniel,Bandera-Delgado Arfy,Huerta-Padilla Victor,Serna-Reyna Luis,Gómez-Gutiérrez Guillermo,Gómez-Virgilio Laura,Bandala Cindy,López-Romero Ricardo,Garrido-Guerrero Efraín,Chanona-Pérez Jorge,Salcedo Mauricio Archives of medical research BACKGROUND:Cervical Cancer (CC) is a worldwide public health concern associated with genetic alterations, among these the gain of the 19q chromosome harboring the Pregnancy Specific Glycoproteins (PSG) gene family. These proteins play a critical role in pregnancy, with participation in immunotolerance, angiogenesis, and invasion processes, which are also observed in carcinogenesis. The aim of this study was to determine the molecular alterations of PSG1 and its relationship with CC. METHODS:PSG1 Copy Number Variation (CNV) was evaluated in 31 CC and eight normal cervical tissues by qPCR. PSG1 expression was correlated with HPV detection and IL-10 and TGF-β expression in CC samples. Finally, PSG1 protein expression was evaluated by immunofluorescence in CC cell lines, by immunohistochemistry in a tissue microarray, and by immunoblotting in the sera of women with normal cervix, pre-invasive lesions, and CC. RESULTS:PSG1 showed a gain of 25.6% in CNV and gene expression in CC. There was a lack of PSG1 expression in normal cervical epithelium and positive immunostaining in 57% of CC tissues, while all CC cell lines expressed PSG1. Finally, PSG1 was immunodetected in 90% of pre-invasive lesions and in all CC serum samples, but not in healthy women. PSG1 expression correlates with the expression of IL-10 and TGF-β in CC tissues, but not with the presence of HPV. CONCLUSION:These data show evidence of the differential expression of PSG1 in CC that could explain its participation in tumor-biology and immunotolerance mechanisms. Further, its immunodetection could provide early detection of this cancer. 10.1016/j.arcmed.2020.05.025
    Pregnancy-specific glycoprotein 1 (PSG1) activates TGF-β and prevents dextran sodium sulfate (DSS)-induced colitis in mice. Blois S M,Sulkowski G,Tirado-González I,Warren J,Freitag N,Klapp B F,Rifkin D,Fuss I,Strober W,Dveksler G S Mucosal immunology Transforming growth factor-βs (TGF-βs) are secreted from cells as latent complexes and the activity of TGF-βs is controlled predominantly through activation of these complexes. Tolerance to the fetal allograft is essential for pregnancy success; TGF-β1 and TGF-β2 play important roles in regulating these processes. Pregnancy-specific β-glycoproteins (PSGs) are present in the maternal circulation at a high concentration throughout pregnancy and have been proposed to have anti-inflammatory functions. We found that recombinant and native PSG1 activate TGF-β1 and TGF-β2 in vitro. Consistent with these findings, administration of PSG1 protected mice from dextran sodium sulfate (DSS)-induced colitis, reduced the secretion of pro-inflammatory cytokines, and increased the number of T regulatory cells. The PSG1-mediated protection was greatly inhibited by the coadministration of neutralizing anti-TGF-β antibody. Our results indicate that proteins secreted by the placenta directly contribute to the generation of active TGF-β and identify PSG1 as one of the few known biological activators of TGF-β2. 10.1038/mi.2013.53
    Human pregnancy specific beta-1-glycoprotein 1 (PSG1) has a potential role in placental vascular morphogenesis. Ha Cam T,Wu Julie A,Irmak Ster,Lisboa Felipe A,Dizon Anne M,Warren James W,Ergun Suleyman,Dveksler Gabriela S Biology of reproduction Previous studies suggest that human pregnancy specific beta-1-glycoproteins (PSGs) play immunomodulatory roles during pregnancy; however, other possible functions of PSGs have yet to be explored. We have observed that PSGs induce transforming growth factor beta 1 (TGFB1), which among its other diverse functions inhibits T-cell function and has proangiogenic properties. The present study investigates a potential role for PSG1, the most abundant PSG in maternal serum, as a possible inducer of proangiogenic growth factors known to play an important role in establishment of the vasculature at the maternal-fetal interface. To this end, we measured TGFB1, vascular endothelial growth factors (VEGFs) A and C, and placental growth factor (PGF) protein levels in several cell types after PSG1 treatment. In addition, tube formation and wound healing assays were performed to investigate a possible direct interaction between PSG1 and endothelial cells. PSG1 induced up-regulation of both TGFB1 and VEGFA in human monocytes, macrophages, and two human extravillous trophoblast cell lines. We did not observe induction of VEGFC or PGF by PSG1 in any of the cells tested. PSG1 treatment resulted in endothelial tube formation in the presence and absence of VEGFA. Site-directed mutagenesis was performed to map the essential regions within the N-domain of PSG1 required for functional activity. We found that the aspartic acid at position 95, previously believed to be required for binding of PSGs to cells, is not required for PSG1 activity but that the amino acids implicated in the formation of a salt bridge within the N-domain are essential for PSG1 function. 10.1095/biolreprod.109.082412
    Induction and activation of latent transforming growth factor-β1 are carried out by two distinct domains of pregnancy-specific glycoprotein 1 (PSG1). Ballesteros Angela,Mentink-Kane Margaret M,Warren James,Kaplan Gerardo G,Dveksler Gabriela S The Journal of biological chemistry Pregnancy-specific glycoproteins (PSGs) are a family of Ig-like proteins secreted by specialized placental cells. The PSG1 structure is composed of a single Ig variable region-like N-terminal domain and three Ig constant region-like domains termed A1, A2, and B2. Members of the human and murine PSG family have been shown to induce anti-inflammatory cytokines from monocytes and macrophages and to stimulate angiogenesis. We recently showed that recombinant forms of PSG1 (PSG1-Fc and PSG1-His) and PSG1 purified from the serum of pregnant women are associated with the immunoregulatory cytokine TGF-β1 and activated latent TGF-β1. Here, we sought to examine the requirement of specific PSG1 domains in the activation of latent TGF-β1. Plasmon surface resonance studies showed that PSG1 directly bound to the small latent complex and to the latency-associated peptide of TGF-β1 and that this binding was mediated through the B2 domain. Furthermore, the B2 domain alone was sufficient for activating the small latent complex. In separate experiments, we found that the PSG1-mediated induction of TGF-β1 secretion in macrophages was dependent on the N-terminal domain. Mutagenesis analysis revealed that four amino acids (LYHY) of the CC' loop of the N-terminal domain were required for induction of latent TGF-β1 secretion. Together, our results show that two distinct domains of PSG1 are involved in the regulation of TGF-β1 and provide a mechanistic framework for how PSGs modulate the immunoregulatory environment at the maternal-fetal interface for successful pregnancy outcome. 10.1074/jbc.M114.597518
    Targeting PSG1 to enhance chemotherapeutic efficacy: new application for anti-coagulant the dicumarol. He Dong-Xu,Gu Feng,Wu Jian,Gu Xiao-Ting,Lu Chun-Xiao,Mao Ai-Qin,Zhang Guang-Yuan,Ding Zhong-Yang,Wang Jin-Ke,Hao Jun-Jun,Fu Li,Ma Xin Clinical science (London, England : 1979) Chemotherapeutic response is critical for the successful treatment and good prognosis in cancer patients. In this study, we analysed the gene expression profiles of preoperative samples from oestrogen receptor (ER)-negative breast cancer patients with different responses to taxane-anthracycline-based (TA-based) chemotherapy, and identified a group of genes that was predictive. Pregnancy specific beta-1-glycoprotein 1 (PSG1) played a central role within signalling pathways of these genes. Inhibiting PSG1 can effectively reduce chemoresistance via a transforming growth factor-β (TGF-β)-related pathway in ER-negative breast cancer cells. Drug screening then identified dicumarol (DCM) to target the PSG1 and inhibit chemoresistance to TA-based chemotherapy in vitro, in vivo, and in clinical samples. Taken together, this study highlights PSG1 as an important mediator of chemoresistance, whose effect could be diminished by DCM. 10.1042/CS20160536