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Shu Q.,Changning Maternity and Infant Health Hospital | Li W.,Changning Maternity and Infant Health Hospital | Li J.,Fudan University | Wang W.,Fudan University | And 2 more authors.
PLoS ONE | Year: 2014

Overexposure of the fetus to glucocorticoids in gestation is detrimental to fetal development. The passage of maternal glucocorticoids into the fetal circulation is governed by 11beta-Hydroxysteroid Dehydrogenase Type 2 (HSD11B2) in the placental syncytiotrophoblasts. Human chorionic gonadotropin (hCG) plays an important role in maintaining placental HSD11B2 expression via activation of the cAMP pathway. In this study, we investigated the relationship between the activation of the cAMP pathway by hCG and subsequent phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/ 2) or p38 mitogen-activated protein kinase (MAPK) pathways in the regulation of placental HSD11B2 expression in human placental syncytiotrophoblasts. We found that treatment of the placental syncytiotrophoblasts with either hCG or dibutyl cAMP (dbcAMP) could promote the phosphorylation of p38 and ERK1/2. Inhibition of p38 MAPK with SB203580 not only reduced the basal HSD11B2 mRNA and protein levels but also attenuated HSD11B2 levels induced by either hCG or dbcAMP. By contrast, inhibition of ERK1/2 with PD98059 increased the basal mRNA and protein levels of HSD11B2 and had no effect on HSD11B2 mRNA and protein levels induced by either hCG or dbcAMP. These data suggest that p38 MAPK is involved in both basal and hCG/cAMP-induced expression of HSD11B2, and ERK1/2 may play a role opposite to p38 MAPK at least in the basal expression of HSD11B2 in human placental syncytiotrophoblasts and that there is complicated cross-talk between hCG/cAMP and MAPK cascades in the regulation of placental HSD11B2 expression. © 2014 Shu et al.


Li J.,Fudan University | Wang W.,Fudan University | Liu C.,Fudan University | Li W.,Changning Maternity and Infant Health Hospital | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Context: Fetal overexposure to glucocorticoids leads to growth restriction. Optimal fetal glucocorticoid level is ensured by the expression of cortisol-inactivating enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) in placental syncytiotrophoblasts. The transcription factor selective promoter factor 1 (Sp1) is known to up-regulate 11β-HSD2 expression in the presence of enhanced histone acetylation in syncytiotrophoblasts, but the mechanisms underlying histone acetylation remain unknown. Objectives: The role of p300 in histone acetylation associated with 11β-HSD2 expression in syncytiotrophoblasts was investigated. Design: Distribution of p300 in human placenta was studied with immunohistochemistry. The role of p300 in histone-3 (H3) acetylation in association with 11β-HSD2 expression was investigated in cultured primary human placental trophoblasts in the presence of small interfering RNA (siRNA)- mediated knockdown of p300, p300 inhibitor C646, or p300 overexpression. The interaction of Sp1 and p300 was studied with chromatin immunoprecipitation and coimmunoprecipitation. Results: Intense staining of p300 was found in the nuclei of trophoblasts. Levels of p300 and acetyl H3K9 and H3K27 associated with 11β-HSD2 promoter were increased in the course of syncytialization and by cAMP pathway activation. Chromatin immunoprecipitation and coimmunoprecipitation revealed p300 and Sp1 on 11β-HSD2 promoter and in the same protein complex in the syncytiotrophoblasts. Overexpression of p300 enhanced 11β-HSD2 expression, which was attenuated by Sp1 knockdown, whereas p300 knockdown and C646 reduced both basal and cAMP-stimulated acetylation of H3K9 and H3K27 associated with 11β-HSD2 expression. Conclusions: Interaction of p300 with Sp1 plays a crucial role in histone acetylation associated with 11β-HSD2 expression in syncytiotrophoblasts, which may have important implications in the establishment of the placental glucocorticoid barrier in gestation. Copyright © 2013 by The Endocrine Society.


Liu C.,Fudan University | Zhu P.,No401 Hospital | Wang W.,Shanghai JiaoTong University | Li W.,Changning Maternity and Infant Health Hospital | And 5 more authors.
Molecular and Cellular Endocrinology | Year: 2016

The underlying mechanism leading to rupture of the membranes at parturition is not fully understood. Lysyl oxidase (LOX) cross-links collagen fibrils thereby increasing the tensile strength of the membranes. Thus, understanding the regulation of LOX expression may be of crucial importance for elucidation of the process of rupture of the fetal membranes. Prostaglandin E2 (PGE2), mainly produced in the amnion, plays crucial roles during human parturition. However it is not known whether PGE2 regulates LOX expression in the fetal membranes. Using primary human amnion fibroblasts, we showed that addition of PGE2 decreased LOX mRNA and protein levels, which were blocked by inhibition of EP2/EP4 receptors and the receptor-coupled cAMP/PKA pathway. EP2/EP4 receptor agonists and stimulators of the cAMP/PKA pathway consistently decreased LOX expression. Furthermore, PGE2 induced cyclo-oxygenase-2 (COX-2) expression, a key enzyme in PGE2 production, via an EP2 and EP4 receptor-coupled cAMP/PKA pathway. Small interfering RNA-mediated knock-down of COX-2 expression significantly increased the basal expression of LOX. In addition, an increase in COX-2 and a reciprocal decrease in LOX abundance occurred in amnion tissue following labor at term. In conclusion, we have revealed a feed-forward loop of induction of COX-2 and reduction in LOX expression by PGE2 acting via an EP2/EP4 receptor-coupled cAMP/PKA pathway in human amnion fibroblasts toward the end of gestation, which may play a significant role in the rupture of fetal membranes. © 2016 Elsevier Ireland Ltd.


PubMed | Fudan University, Shanghai JiaoTong University and Changning Maternity and Infant Health Hospital
Type: Journal Article | Journal: PloS one | Year: 2014

Overexposure of the fetus to glucocorticoids in gestation is detrimental to fetal development. The passage of maternal glucocorticoids into the fetal circulation is governed by 11beta-Hydroxysteroid Dehydrogenase Type 2 (HSD11B2) in the placental syncytiotrophoblasts. Human chorionic gonadotropin (hCG) plays an important role in maintaining placental HSD11B2 expression via activation of the cAMP pathway. In this study, we investigated the relationship between the activation of the cAMP pathway by hCG and subsequent phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) or p38 mitogen-activated protein kinase (MAPK) pathways in the regulation of placental HSD11B2 expression in human placental syncytiotrophoblasts. We found that treatment of the placental syncytiotrophoblasts with either hCG or dibutyl cAMP (dbcAMP) could promote the phosphorylation of p38 and ERK1/2. Inhibition of p38 MAPK with SB203580 not only reduced the basal HSD11B2 mRNA and protein levels but also attenuated HSD11B2 levels induced by either hCG or dbcAMP. By contrast, inhibition of ERK1/2 with PD98059 increased the basal mRNA and protein levels of HSD11B2 and had no effect on HSD11B2 mRNA and protein levels induced by either hCG or dbcAMP. These data suggest that p38 MAPK is involved in both basal and hCG/cAMP-induced expression of HSD11B2, and ERK1/2 may play a role opposite to p38 MAPK at least in the basal expression of HSD11B2 in human placental syncytiotrophoblasts and that there is complicated cross-talk between hCG/cAMP and MAPK cascades in the regulation of placental HSD11B2 expression.


PubMed | Fudan University, Oregon Health And Science University, Shanghai JiaoTong University, No401 Hospital and Changning Maternity and Infant Health Hospital
Type: | Journal: Molecular and cellular endocrinology | Year: 2016

The underlying mechanism leading to rupture of the membranes at parturition is not fully understood. Lysyl oxidase (LOX) cross-links collagen fibrils thereby increasing the tensile strength of the membranes. Thus, understanding the regulation of LOX expression may be of crucial importance for elucidation of the process of rupture of the fetal membranes. Prostaglandin E2 (PGE2), mainly produced in the amnion, plays crucial roles during human parturition. However it is not known whether PGE2 regulates LOX expression in the fetal membranes. Using primary human amnion fibroblasts, we showed that addition of PGE2 decreased LOX mRNA and protein levels, which were blocked by inhibition of EP2/EP4 receptors and the receptor-coupled cAMP/PKA pathway. EP2/EP4 receptor agonists and stimulators of the cAMP/PKA pathway consistently decreased LOX expression. Furthermore, PGE2 induced cyclo-oxygenase-2 (COX-2) expression, a key enzyme in PGE2 production, via an EP2 and EP4 receptor-coupled cAMP/PKA pathway. Small interfering RNA-mediated knock-down of COX-2 expression significantly increased the basal expression of LOX. In addition, an increase in COX-2 and a reciprocal decrease in LOX abundance occurred in amnion tissue following labor at term. In conclusion, we have revealed a feed-forward loop of induction of COX-2 and reduction in LOX expression by PGE2 acting via an EP2/EP4 receptor-coupled cAMP/PKA pathway in human amnion fibroblasts toward the end of gestation, which may play a significant role in the rupture of fetal membranes.


Xue Y.,Papillomavirus Regulation and Cancer | Bellanger S.,Papillomavirus Regulation and Cancer | Zhang W.,Changning Maternity and Infant Health Hospital | Lim D.,National University Hospital Singapore | And 3 more authors.
Cancer Research | Year: 2010

The viral E2 gene product plays a crucial role in the human papillomavirus (HPV) vegetative cycle by regulating both transcription and replication of the viral genome. E2 is a transcriptional repressor of the E6 and E7 viral oncogenes for HPV types 16 and 18, which are involved in cervical cancers. Using new polyclonal antibodies against the HPV16 E2 protein, we showed that E2 is expressed at various precursor stages of cervical carcinoma by immunohistochemistry on paraffin-embedded clinical samples. E2 was found to be highly expressed in the nuclei and cytoplasm of cells forming the intermediate and upper layers of cervical intraepithelial neoplasia (CIN). We could show that the expressions of E2 and p16INK4a (surrogate marker for oncogenic E7 expression) were exclusive in most of the cases, thus implying that E2 is not expressed together with high levels of E7. Moreover, we found that E2 is expressed in a subset of columnar cells adjacent to the CIN. We could show that expression of E2 is topologically distinct from the proliferation markers p63 and Ki67, whereas it coincides with the expression of cytokeratin K13, a marker of squamous cell differentiation. Expression of E2 also topologically coincides with episomal amplification of viral genomes in the upper layers of CIN1. These in vivo data thus validate previous assumptions of the crucial role of E2 in the early steps of HPV infection and of its negative link with expression of the viral E6 and E7 oncogenes. ©2010 AACR.


Liu P.,Changning Maternity and Infant Health Hospital | Wang C.,Changning Maternity and Infant Health Hospital | Ma C.,Changning Maternity and Infant Health Hospital | Wu Q.,Changning Maternity and Infant Health Hospital | And 2 more authors.
Cancer Cell International | Year: 2016

Background: To investigate the role of total cellular microRNA (miRNA) in regulating epithelial-to-mesenchymal transition (EMT) during human endometrial endometrioid adenocarcinoma (EEC). Methods: A miRCURY LNA microRNA array was used to evaluate the miRNA profiles of human EEC tissues and corresponding nontumorous endometriums. An in vitro model of TGF-β induced EMT in HEC-1-A cells was used to investigate the role of miRNAs in the EEC during EMT. The expression of SMAD3, SMAD5, and a panel of EMT markers was detected by Western blot and quantitative PCR. Results: The results of miRNA profiling in human EEC tissues and corresponding nontumorous endometriums demonstrated that miR-23a expression was down-regulated. Using bioinformatics, we identified SMAD3 or SMAD5 maybe as a predicted target of miR-23a. The results of luciferase reporter assay showed miR-23a directly targets and down-regulates human SMAD3 protein levels, not SMAD5 protein levels. Furthermore, overexpression of miR-23a in HEC-1-A cells increased E-cadherin expression and decreased the expression of vimentin and alpha smooth muscle actin, markers of mesenchymal cellular phenotype. Conclusions: Our data provide firm evidence of a role for miR-23a in the direct regulation of EMT through its targeting of SMAD3. Due to its ability to repress the EMT, miR-23a may be a novel target for EER therapeutic intervention. © 2016 The Author(s).


Zhang W.Y.,Changning Maternity and Infant Health Hospital
Zhonghua fu chan ke za zhi | Year: 2010

To study the clearance of high risk human papillomavirus (HPV) infection among the women with normal cervical pathologic diagnosis. One hundred and seventy-two HPV-positive cases with normal cervical pathologic diagnosis were enrolled in the study. The infection status of HPV was monitored during follow-up from Aug 2006 to Aug 2008. The time of HPV infection spontaneous clearance, as well as effect factors, were analyzed. During follow-up, there were 62.2% (107 cases, 107/172) of the HPV infection cleared. The medium clearance time was 11.3 months (95%CI: 10.6 - 16.6 months). The medium clearance time of aged < 30 years, 30 - 39 years, 40 - 49 years and > 49 years were 11.3, 12.0, 10.9 and 8.5 months, respectively. There were not significant difference among aged intervals (P = 0.384). The virus copies of HPV-clearance cases and persistent-infection were 22.6 and 95.0, respectively. There was not significant difference between groups (P = 0.061). Most of the high risk HPV infection with normal cervical pathologic diagnosis would spontaneously cleared. Age and HPV copies may play little role in the HPV clearance.


Liu P.,Changning Maternity and Infant Health Hospital | Qi M.,Chinese Academy of Sciences | Ma C.,Changning Maternity and Infant Health Hospital | Lao G.,Changning Maternity and Infant Health Hospital | Liu Y.,Changning Maternity and Infant Health Hospital
FEBS Letters | Year: 2013

MicroRNAs negatively regulate target gene expression at the post-transcriptional level during carcinogenesis. Recent advances revealed that the expression levels of several miRNAs are up- or down-regulated in endometrial carcinoma (EC). Here we identify dysregulated miRNAs in EC and we elucidate the essential role of let-7a. The expression of 86 miRNAs in EC was found to be different from adjacent normal endometrial tissues. Moreover, miR-let-7 members are down-regulated in EC and let-7 miRNAs are highly associated with endometrial cancer. A functional investigation revealed that let-7a suppressed proliferation of HeLa cells by targeting Aurora-B. Let-7a also antagonizes Aurora-B functions in promoting carcinoma cell proliferation by down-regulating Aurora-B protein level. Let-7a could be applied for gene therapy against endometrial carcinogenesis. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.


PubMed | Changning Maternity and Infant Health Hospital
Type: Journal Article | Journal: FEBS letters | Year: 2013

MicroRNAs negatively regulate target gene expression at the post-transcriptional level during carcinogenesis. Recent advances revealed that the expression levels of several miRNAs are up- or down-regulated in endometrial carcinoma (EC). Here we identify dysregulated miRNAs in EC and we elucidate the essential role of let-7a. The expression of 86 miRNAs in EC was found to be different from adjacent normal endometrial tissues. Moreover, miR-let-7 members are down-regulated in EC and let-7 miRNAs are highly associated with endometrial cancer. A functional investigation revealed that let-7a suppressed proliferation of HeLa cells by targeting Aurora-B. Let-7a also antagonizes Aurora-B functions in promoting carcinoma cell proliferation by down-regulating Aurora-B protein level. Let-7a could be applied for gene therapy against endometrial carcinogenesis.

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