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PubMed2006

Glycodelin mediates the increase in vascular endothelial growth factor in response to oxidative stress in the endometrium.

OBJECTIVE: We hypothesized that glycodelin stimulates vascular endothelial growth factor (VEGF) expression in response to oxidative stress. STUDY DESIGN: EM42 (human endometrial epithelial cell line) and primary endometrial epithelial cells were subjected to oxidative stress with minimally oxidized low density lipoprotein (mLDL). Cells were also incubated with no LDL (control) or native LDL (nLDL). Each condition was incubated with and without glycodelin antibody. Glycodelin and VEGF protein and messenger RNA (mRNA) levels were analyzed. Primary cells were cultured with glycodelin peptide to evaluate the effect on VEGF protein and mRNA. RESULTS: Glycodelin and VEGF protein and mRNA were higher for cells grown with mLDL (P < .05), while glycodelin antibody attenuated the increase in VEGF protein (P < .01). Glycodelin peptide increased VEGF mRNA and protein (P < .05). CONCLUSION: Glycodelin may act as an autocrine factor within endometriotic implants to increase VEGF expression during oxidative stress.

Antibodies↗
PubMed2000

Effects of progestins and relaxin on glycodelin gene expression in human endometrial cells.

OBJECTIVE: Glycodelin is an endometrial protein proposed to play an important role in embryonic implantation. We examined the effects of progestins and relaxin on glycodelin transcription, synthesis, and secretion. STUDY DESIGN: Northern blotting, metabolic labeling, and fluorography were used to assess glycodelin messenger ribonucleic acid and protein synthesis in endometrial tissue and cells. Luciferase reporter constructs transfected into endometrial adenocarcinoma cells (Ishikawa cells) were used to determine whether progestins or relaxin could activate the glycodelin gene promoter. RESULTS: Progestins but not relaxin stimulated glycodelin secretion in primary epithelial cell cultures. A 452-base pair fragment of the glycodelin gene promoter was activated 4.3 +/- 0.7 times normal by 10-nmol/L promegestone; however, addition of relaxin to the same construct repressed progestin-stimulate promoter activation by >30%. CONCLUSION: Glycodelin transcription, synthesis, and secretion by endometrial epithelial cells were stimulated by progestins. However, relaxin failed to stimulate production of this immunomodulatory protein and, in fact, repressed progestin-stimulated activation of the glycodelin gene promoter.

Endometrium↗
PubMed1999

Glycodelin and beta-lactoglobulin, lipocalins with a high structural similarity, differ in ligand binding properties.

Human glycodelin, a lipocalin with a high amino acid similarity to beta-lactoglobulins, appears as various glycoforms with different biological activities in endometrium (glycodelin-A) and seminal plasma (glycodelin-S). We found that the structures of these glycodelins and beta-lactoglobulin are similar. Despite this structural similarity, unlike beta-lactoglobulin, glycodelin-A binds neither retinoic acid nor retinol. It was impossible to detect any endogenous retinoids or steroids in any of the two purified glycodelins. Both their glycoforms share similar thermodynamic parameters of reversible denaturation suggesting that native folding of glycodelin-A and glycodelin-S is not influenced by the differences in glycosylation or by ligand binding.

Base Sequence↗
PubMed2000

Implications in the maintenance of pregnancy: I. Presence of immunoreactive glycodelin in human umbilical cord vein endothelial cells.

OBJECTIVE: We previously reported an antipeptide antibody to human glycodelin that recognizes glycodelin in amniotic fluid and epithelial glands of the endometrium. The objective of this study was to determine the presence of glycodelin in human umbilical cord. DESIGN: Controlled clinical study. SETTING: Healthy women undergoing normal delivery at Grady Memorial Hospital, Atlanta, Georgia. PATIENT(S): Healthy women undergoing normal delivery. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Umbilical cord vein was isolated from the cord and used for immunohistochemical studies. Human umbilical cords and placentae were collected after full-term delivery. Cords were washed and fixed with formal sucrose. Decidua tissues and blood vessels from placentae were dissected out and fixed. Cryostat sections were immunostained with anti-glycodelin peptide antibody and anti-von Willebrand factor antibody. RESULT(S): Endothelial cells of human umbilical cord vein and artery were strongly immunostained with antiglycodelin antibody. Endothelial cells of the vein were more strongly stained than those of the artery. These cells were confirmed as endothelial cells by positive immunostaining with anti-von Willebrand factor. The epithelial cells outlining the cord were stained with antiglycodelin antibody but not with anti-von Willebrand factor antibody. CONCLUSION(S): This is the first study showing that immunoreactive glycodelin is present in endothelial cells of the umbilical cord. Glycodelin in the umbilical cord may have immunosuppressive or other, unknown functions affecting the physiology or pathophysiology of pregnancy. Whether umbilical vein endothelial cells synthesize glycodelin or serve as reservoir for glycodelin is currently under investigation.

Case-Control Studies↗
PubMed2005

Expression of glycodelin protein and mRNA in human ductal breast cancer carcinoma in situ, invasive ductal carcinomas, their lymph node and distant metastases, and ductal carcinomas with recurrence.

Glycodelin, previously known as PP14, has been localized in endometrial, ovarian and cervical carcinoma cells. Recently, glycodelin was demonstrated to be expressed in cancerous human breast tissue. In this study, paraffin-embedded slides of carcinoma in situ, invasive carcinomas without metastases, invasive carcinomas with corresponding lymph node metastases, invasive carcinomas with corresponding recurrence and invasive carcinomas with corresponding distant metastases were investigated for glycodelin protein and mRNA expression. Protein expression was found in all cases of carcinoma in situ, in invasive carcinoma without lymph node metastases in 90% of cases, in breast cancer with lymph node metastases in 50% of cases, in breast cancer with recurrence in 38% of cases and in breast cancer with distant metastases in 40% of cases. Results were confirmed by in situ hybridization showing reduced glycodelin expression as lymph node metastasis progressed, compared to carcinoma in situ. Glycodelin mRNA expression is not further reduced in carcinomas with distant metastasis and recurrence compared to carcinoma in situ. Results demonstrate that invasive breast carcinomas without metastases are more likely to express glycodelin. In contrast, cases of breast cancer with metastatic infiltration and recurrence show weak expression of glycodelin. On the basis of these results, we speculate that glycodelin could be used as a prognostic marker for breast cancer.

Adult↗
PubMed1997

Expression of glycodelin in MCF-7 breast cancer cells induces differentiation into organized acinar epithelium.

Glycodelin, a 28-kd human glycoprotein found in glandular epithelial cells of endometrium and seminal vesicle, was originally considered specific for the reproductive tract. Glycodelin has significant amino-acid sequence homology with beta-lactoglobulins from various species. We report herein the expression of glycodelin in normal and neoplastic glandular epithelia outside the reproductive tract including breast, sweat glands, parabronchial glands, hidradenoma, and pancreatic cystadenoma. The localization of glycodelin in highly differentiated acinar epithelia led us to investigate a possible role for glycodelin in epithelial organization. Transfection of glycodelin cDNA into MCF-7 breast cancer cells induced a dramatically altered growth behavior with formation of acinar configurations and an inability to grow in semisolid media because of apoptosis. The glycodelin-expressing cells also displayed strongly up-regulated expression of markers of organized epithelia, such as cytokeratins 8 and 18 as well as E-cadherin, and changes in intracellular distribution of beta-catenin. The rate of proliferation was also suppressed. These results show that, besides being a product of glandular epithelial cells, expression of glycodelin is accompanied by the acquisition of a phenotype of organized glandular epithelium.

Breast Neoplasms↗
PubMed2005

Expression of glycodelin A in decidual tissue of preeclamptic, HELLP and intrauterine growth-restricted pregnancies.

During pregnancy, the placenta produces a variety of proteins that are responsible for the establishment of the foeto-maternal tolerance and circulation. The aim of this study was to investigate the expression of glycodelin A (formerly named PP14) in decidual tissue of placentas with intrauterine growth restriction (IUGR), preeclamptic patients, hemolysis, elevated liver, low-platelet (HELLP) patients and normal decidual tissue. Slides of paraffin-embedded decidual tissue of patients with IUGR, preeclamptic patients, HELLP patients and normal-term placentas were incubated with either polyclonal or monoclonal antibodies against glycodelin A. Staining reaction was performed with the ABC reagent. Intensity of immunohistochemical reaction on the slides was analysed using a semi-quantitative score. In addition, expression of glycodelin mRNA was analysed by in situ hybridisation. Expression of glycodelin A was significantly reduced in decidual cells of placentas with IUGR and HELLP, as investigated with both monoclonal and polyclonal antibodies and in situ hybridisation. However, preeclamptic decidual tissue showed no significantly different expression of intensity of glycodelin mRNA compared with normal placental tissue controls. A reduced expression of glycodelin A by decidual cells seems to be related to IUGR and HELLP. Therefore, glycodelin A might play an important role in the pathogeneses of these diseases.

Adult↗
PubMed2005

Late follicular phase administration of levonorgestrel as an emergency contraceptive changes the secretory pattern of glycodelin in serum and endometrium during the luteal phase of the menstrual cycle.

This study examined serum glycodelin concentrations and endometrial expression during the luteal phase following oral administration of levonorgestrel (LNG) at different stages of the ovarian cycle. Thirty women were recruited and allocated into three groups. All groups were studied during two consecutive cycles, a control cycle and the treatment cycle. In the treatment cycle, each woman received two doses of 0.75 mg LNG taken 12 h apart on days 3-4 before the luteinizing hormone (LH) surge (Group 1), at the time of LH rise (Group 2) and 48 h after the rise in LH was detected (Group 3). Serum progesterone (P) and glycodelin were measured daily during the luteal phase, and an endometrial biopsy was taken at day LH +9 for immunohistochemical glycodelin-A staining. In Group 1, serum P levels were significantly lower, serum glycodelin levels rose earlier and endometrial glycodelin-A expression was weaker than in Groups 2 and 3, in which no differences were found between control and treatment cycles. Levonorgestrel taken for emergency contraception (EC) prior to the LH surge alters the luteal phase secretory pattern of glycodelin in serum and endometrium. Based on the potent gamete adhesion inhibitory activity of glycodelin-A, the results may account for the action of LNG in EC in those women who take LNG before the LH surge.

Adult↗
PubMed2001

Angiogenic role for glycodelin in tumorigenesis.

Angiogenesis plays an important role in neovascularization in tumors. Glycodelin, a hormone-responsive protein, has been detected in tumors of reproductive organs and is found in high levels in the plasma of subjects with gynecological malignancies. Glycodelin is also found in the endothelial cells of the umbilical cord and in the blood vessels of tumors. In this study, we tested whether glycodelin-rich amniotic fluid and a synthetic peptide derived from the sequence of glycodelin peptide (Gp) might promote angiogenic response by examining the migration and tube formation in human umbilical cord vein endothelial cells (HUVECs). Increased migration and tube formation of HUVECs were found in the presence of amniotic fluid and Gp, and this increase was blocked by antibody to Gp and by an anti-vascular endothelial growth factor (VEGF) antibody, suggesting that the angiogenic effects of glycodelin might be mediated by VEGF. The results also showed that Gp significantly increased the release of VEGF protein and mRNA expression in HUVECs, RL-95 (human endometrial carcinoma cells), OVCAR-3 (human ovarian adenocarcinoma cells), EM42 (human endometrial epithelial cells), THP-1 (human monocyte), and MCF-7 and MDA-MB-231 (human breast adenocarcinoma cells) cell lines. VEGF receptor Fit-1 mRNA expression in HUVECs was also increased in the presence of Gp. These findings, together with the suggestion from the literature that glycodelin may have immunosuppressive properties, suggest that glycodelin might play an important role in neovascularization during embryogenesis and tumor development.

Amino Acid Sequence↗
PubMed2002

The synthesis and fate of glycodelin in human ovary during folliculogenesis.

The ontogeny of glycodelin in human ovarian follicles during folliculogenesis was studied. Glycodelin immunoreactivity began to be detected in the granulosa cells and thecal cells of late secondary follicles. Immunoreactivity was also found in both the luteinized granulosa cells and cumulus cells obtained from women undergoing the assisted reproduction treatment. However, only the luteinized granulosa cells, and not the cumulus cells, expressed glycodelin mRNA. Results also showed that the cumulus cells took up radiolabelled glycodelin and partially deglycosylated some of it. Glycodelin (and a partially deglycolsylated form of glycoldelin) appeared to complex with two cytoplasmic or membrane components of the cumulus cells. The data also demonstrated that ZIF-1, a glycoprotein isolated from human follicular fluid, was immunologically similar to glycodelin. In conclusion, we suggest that glycodelin is synthesized in the granulosa cells of ovarian follicles at late secondary follicle stage. It then may be released into the follicular fluid from where it is taken up and partially modified by the cumulus cells.

Binding, Competitive↗
PubMed2006

Histone deacetylase inhibitors stimulate cell migration in human endometrial adenocarcinoma cells through up-regulation of glycodelin.

Histone deacetylase inhibitors (HDACIs) have recently emerged as promising anticancer drugs to induce cell cycle arrest, cytodifferentiation, and apoptosis. It is suggested, however, that HDACIs promote cell migration and invasion depending on the cell type. We have reported previously that treatment with HDACIs, including trichostatin A and suberoylanilide hydroxamic acid (SAHA) or progesterone in combination with estrogen, can induce cytodifferentiation of endometrial adenocarcinoma Ishikawa cells through up-regulation of glycodelin, a progesterone-induced endometrial glycoprotein. Given the reported role of glycodelin in cell motility and the migration-modulating potential of HDACIs, we investigated using wound healing assay and transwell migration assay whether ovarian steroid hormones, trichostatin A, or SAHA affects cell migration in endometrial cancer cell lines, Ishikawa and RL95-2. Treatment with ovarian steroid hormones, trichostatin A, and SAHA enhanced cell migration together with up-regulation of glycodelin. SAHA-augmented cell migration was almost completely blocked by gene silencing of glycodelin. Furthermore, overexpression of gycodelin alone resulted in increased cell motility in Ishikawa cells. Our results collectively indicate that glycodelin positively regulates cell motility acting as a mediator of HDACI-enhanced endometrial cell migration, suggesting the involvement of glycodelin in the dynamic endometrial gland morphogenesis during menstrual cycle. Our results raise a possibility that the use of HDACIs in the therapy for glycodelin-inducible endometrial and presumably other gynecological cancers may enhance invasion in cases in which the HDACIs fail to exert differentiation-inducing and/or antiproliferative effects.

Adenocarcinoma↗
PubMed2004

Reduced serum glycodelin and insulin-like growth factor-binding protein-1 in women with polycystic ovary syndrome during first trimester of pregnancy.

The polycystic ovary syndrome (PCOS) is associated with an increased rate of early pregnancy loss (EPL). Hyperinsulinemia is an independent risk factor for EPL and has been found to decrease levels of glycodelin and IGF binding protein-1 (IGFBP-1), two major endometrial proteins. We hypothesized that serum glycodelin IGFBP-1 concentrations would be reduced in women with PCOS during the first trimester of pregnancy. Fasting serum insulin, glycodelin, and IGFBP-1 were measured, and oral glucose tolerance tests were performed in 72 women with PCOS and 62 normal women. Each woman was seen once and assigned to one of three gestational groups: wk 3-5, 6-8, and 9-11. The insulin sensitivity index during oral glucose tolerance test was lower in women with PCOS compared with normal women throughout the first trimester (P < 0.0001). Both serum glycodelin and IGFBP-1 were markedly lower in women with PCOS (for glycodelin: wk 3-5, P < 0.0001; wk 6-8, P = 0.03; wk 9-11, P = 0.19; and for IGFBP-1: wk 3-5 and 6-8, P < 0.0001; wk 9-11, P = 0.0003). Comparing women with PCOS who experienced EPL with those who did not, serum glycodelin was significantly lower during wk 3-8 (P < 0.02) and serum IGFBP-1 during wk 9-11 (P = 0.003). During the first trimester, serum glycodelin and IGFBP-1 concentrations are markedly decreased in PCOS, implicating endometrial epithelial and stromal dysfunction during periimplantation and early pregnancy as a possible mechanism for EPL in PCOS. These decreases are likely to be secondary to hyperinsulinemia and reduced insulin sensitivity.

Abortion, Spontaneous↗
PubMed1998

Promegestone (R5020) and mifepristone (RU486) both function as progestational agonists of human glycodelin gene expression in isolated human epithelial cells.

One of the most abundant protein products of human secretory endometrium is glycodelin, a glycoprotein previously referred to as PP14. Although the precise function of this protein is unknown, its unique glycosylation pattern is believed to affect immunomodulatory activity during human embryonic implantation and inhibition of sperm-egg binding after ovulation. Having confirmed the expression of glycodelin in secretory endometrial glands, we used purified endometrial epithelial cell cultures to demonstrate the hormonal regulation of glycodelin synthesis and secretion. The findings were corroborated by transiently transfecting glycodelin gene promoter-reporter constructs into human epithelioid HeLa and Ishikawa cells. Our results indicate that glycodelin protein production by endometrial epithelial cells is directly up-regulated 4- to 9-fold by progestins and antiprogestins in vitro. Transcriptional regulation of the glycodelin gene promoter expressed in HeLa cells is progesterone receptor-dependent. As observed in the primary endometrial cells, progestins and antiprogestins both act as agonists on the in vitro expression of this endometrial gene. Our findings provide insight into the regulation of this abundant endometrial protein and raise interesting questions about the physical nature of the interaction of agonist- and antagonist-bound progesterone receptors with the glycodelin gene promoter.

Drug Evaluation, Preclinical↗
PubMed2005

Stimulation of hCG protein and mRNA in first trimester villous cytotrophoblast cells in vitro by glycodelin A.

AIM: Human chorionic gonadotropin (hCG) is produced by fetal trophoblast cells and secreted into maternal circulation mainly in the first trimester of pregnancy. Another glycoprotein, glycodelin A, is one of the main products of the maternal decidua during this period. The purpose of this study was to investigate the effect of glycodelin A on hCG release by isolated cytotrophoblast cells in vitro. METHODS: Cytotrophoblast cells were prepared from human first trimester placenta and incubated with varying concentrations of glycodelin A. Supernatants were assayed for hCG protein concentrations, and quantification of beta hCG mRNA was carried out by RT-PCR. Expression of hCG was analysed in stimulated trophoblast cells and in unstimulated controls by immunocytochemistry. RESULTS: Glycodelin A induces a dose-dependent increase of hCG production. An increase of hCG expression was measured at 100 and 200 microg/mL glycodelin-A treatment in trophoblast cell culture by TaqMan assay on mRNA level. We found a moderate staining of hCG in control trophoblast cells, whereas a strong hCG staining was seen in glycodelin A-treated trophoblast cells. CONCLUSIONS: HCG is a marker for the differentiation process of trophoblast cells. Our results suggest that glycodelin A secreted by the decidualized endometrium is involved in the regulation of hormones produced by the trophoblast.

Cells, Cultured↗
PubMed1999

Glycodelin mRNA is expressed in the genital tract of male and female rats (Rattus norvegicus).

In the present study we demonstrate for the first time the expression of glycodelin mRNA in the female and male genital tracts of rats using non-radioactive in situ hybridisation. Glycodelin fragment 1 (+41 to +141) shares 100% homology with the human gene sequence. In the ovary, glycodelin mRNA was restricted to granulosa cells. In the uterus, glycodelin mRNA was expressed in all epithelial cells of the endometrium. In the male reproductive tract, glycodelin mRNA was distributed in all epithelial cells of the epididymis, the prostate and the seminal vesicle. However, in the testis, glycodelin mRNA was predominantly found in spermatogonia and in spermatocytes of the seminiferous epithelium. The expression in several reproductive organs of rats offers an excellent tool to study further the physiological role of glycodelin, which is so far thought to act as an immunosuppressive factor.

Animals↗
PubMed2006

[Glycodelin in IVF-ET cycles: its association with endometrial receptivity and impact on the outcome of pregnancy].

OBJECTIVE: To investigate the correlation between glycodelin and endometrial receptivity and the value of serum glycodelin detection in in vitro fertilization and embryo transfer (IVF-ET) cycles for evaluation of the outcome of pregnancy. METHODS: Serum glycodelin level in women receiving IVF-ET on the day of oocyte retrieval and embryo transfer was measured by ELISA, and the condition of the endometrium was examined by transvaginal ultrasonography. RESULTS: There was no difference in serum glycodelin level on the day of oocyte retrieval or embryo transfer between the pregnant group and nonpregnant group, but the ratio and difference of serum glycodelin levels on the days of embryo transfer and retrieval were both higher in pregnant group than in the nonpregnant group (2.54-/+2.14 vs 0.96-/+0.51, and 0.91-/+1.22 vs -0.30-/+1.14, respectively). No correlation was found between serum glycodelin levels and endometrial thickness or echo patterns. CONCLUSION: Serum glycodelin levels on the days of retrieval and embryo transfer are not correlated to endometrial thickness or echo patterns, but their dynamic changes reflect endometrial receptivity to a certain extent, which might have prognostic value for pregnancy following IVF-ET.

Adult↗
PubMed2000

Glycodelin-A expression in the uterine cervix.

OBJECTIVE: Local immunosuppressive factors in the uterine cervix infected by human papillomavirus are felt to facilitate the malignant transformation process. Glycodelin-A is an immunosuppressive peptide found in several tissues of müllerian origin, most notably the pregnant and decidualized endometrium. Its expression in the uterine cervix has not been defined but could theoretically contribute to the immunopermissive environment of the cervix. To determine whether glycodelin-A is found in the cervix we examined the squamous and endocervical epithelia from both normal and neoplastic cervical specimens from 14 women. METHODS: Immunohistochemisty identification of glycodelin-A was performed on archival paraffin-embedded sections from 10 hysterectomies and 4 cone biopsies. Sections were evaluated and staining was scored as negative, positive, or strongly positive with a separate score for the squamous and glandular components of the cervix. RESULTS: Eleven of 14 cases, 79%, demonstrated positive staining of the squamous epithelium. Glycodelin-positive cases included hisologically normal (n = 4; 3 strongly positive, 1 positive) as well as dysplastic (n = 5; 1 strongly positive, 2 positive, and 2 negative) and malignant squamous cells (n = 5; 1 strongly positive, 3 positive, and 1 negative). Normal glandular epithelia were negative in all cases but 1, which demonstrated significant squamous and tubal metaplasia of the endocervical glands involved. CONCLUSION: Glycodelin-A is found in the squamous epithelium of both the histologically normal and the neoplastic cervix. Further characterization of these results will focus on the possible immunosuppressive effect glycodelin-A may have in the cervix.

Cervix Uteri↗
PubMed2006

Glycodelin A is expressed differentially in normal human endometrial tissue throughout the menstrual cycle as assessed by immunohistochemistry and in situ hybridization.

OBJECTIVE: To [1] evaluate glycodelin A immunolabeling in normal endometrium with specific monoclonal (mAb) and polyclonal peptide (pAb) antibodies, [2] to assess glycodelin messenger RNA (mRNA) by in situ hybridization, and [3] to conduct deglycosylation experiments to evaluate the recognized epitope of the mAb vs. pAb. DESIGN: Retrospective immunohistochemical analysis. SETTING: University institute and hospital in Germany. PATIENT(S): Normal human endometrial tissue from the proliferative (PP), early secretory, and late secretory phases were obtained from patients undergoing surgery for benign diseases. INTERVENTION(S): Generation of a pAb in rabbit, immunohistochemistry, and in situ hybridization. MAIN OUTCOME MEASURE(S): Semiquantitative and computerized analysis. RESULT(S): A statistically significant increase of the glycodelin A immunolabeling in the late secretory phase compared with PP was demonstrated by using the mAb. Polyclonal-peptide antibody immunolabeling also showed a rise between the PP and late secretory phases, but without statistical significance. In situ hybridization demonstrated a statistically significantly higher mRNA content during the early secretory phase compared with during PP. CONCLUSION(S): Glycodelin was demonstrated in normal endometrium at the protein and mRNA levels. The mAb may be more useful in assessing glycodelin expression in endometrium, because it probably can bind to glycodelin A-unique glycan structures, in contrast to the peptide pAb. This is of major interest because it may reveal possible structural and functional relationships in different parts of this molecule and elucidate possible functions of this glycoprotein in human endometrial tissue.

Adult↗