MD/PhD, Tongji University, Clinical Medicine, Ob/Gyn (2015)
MBBS, Tongji University, Clinical Medicine (2012)
Virginia Winn, Postdoctoral Faculty Sponsor
Virginia Winn, Postdoctoral Research Mentor
A novel in vitro stem cell model to study maternal endothelial function in preeclampsia
MOSBY-ELSEVIER. 2023: S10
View details for Web of Science ID 000909337400012
Placental Expression of Stanniocalcin 2 (STC2) in Healthy and Preeclamptic Pregnancies
MOSBY-ELSEVIER. 2023: S92-S93
View details for Web of Science ID 000909337400121
PRC2-mediated epigenetic suppression of type I IFN-STAT2 signaling impairs antitumor immunity in luminal breast cancer.
The immunosuppressive tumor microenvironment in some cancer types, such as luminal breast cancer, supports tumor growth and limits therapeutic efficacy. Identifying approaches to induce an immunostimulatory environment could help improve cancer treatment. Here, we demonstrate that inhibition of cancer-intrinsic EZH2 promotes antitumor immunity in estrogen receptor a-positive (ERa+) breast cancer. EZH2 is a component of the PRC2 complex, which catalyzes trimethylation of histone H3 at lysine 27 (H3K27me3). A 53-gene PRC2 activity signature was closely associated with the immune responses of ERa+ breast cancer cells. The stimulatory effects of EZH2 inhibition on immune surveillance required specific activation of type I interferon (IFN) signaling. Integrative analysis of PRC2-repressed genes and genome-wide H3K27me3 landscape revealed that type I IFN ligands are epigenetically silenced by H3K27me3. Notably, the transcription factor STAT2, but not STAT1, mediated the immunostimulatory functions of type I IFN signaling. Following EZH2 inhibition, STAT2 was recruited to the promoters of IFN-stimulated genes even in the absence of the cytokines, suggesting the formation of an autocrine IFN-STAT2 axis. In patients with luminal breast cancer, high levels of EZH2 and low levels of STAT2 were associated with the worst antitumor immune responses. Collectively, this work paves the way for the development of an effective therapeutic strategy that may reverse immunosuppression in cancer.
View details for DOI 10.1158/0008-5472.CAN-22-0736
View details for PubMedID 36222718
Enhancer RNAs Mediate Estrogen-Induced Decommissioning of Selective Enhancers by Recruiting ERα and Its Cofactor.
2020; 31 (12): 107803
The function of enhancer RNAs (eRNAs) in transcriptional regulation remains obscure. By analyzing the genome-wide nascent transcript profiles in breast cancer cells, we identify a special group of eRNAs that are essential for estrogen-induced transcriptional repression. Using eRNAs of TM4SF1 and EFEMP1 as the paradigms, we find that these RNA molecules not only stabilize promoter-enhancer interactions but also recruit liganded estrogen receptor α (ERα) to particular enhancer regions, facilitate the formation of a functional transcriptional complex, and cause gene silencing. Interestingly, ERα is shown to directly bind with eRNAs by its DNA-binding domain. These eRNAs help with the formation of a specific ERα-centered transcriptional complex and promote the association of the histone demethylase KDM2A, which dismisses RNA polymerase II from designated enhancers and suppresses the transcription of target genes. Our work demonstrates a complete mechanism underlying the action of eRNAs in modulating and refining the locus-specific transcriptional program.
View details for DOI 10.1016/j.celrep.2020.107803
View details for PubMedID 32579929
Maternal and umbilical cord serum-derived exosomes enhance endothelial cell proliferation and migration.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
2018; 32 (8): 4534-4543
We investigated the role of exosomes derived from maternal and umbilical cord blood in the regulation of angiogenesis. We report here that both maternal exosomes (MEs) and umbilical exosomes (UEs) significantly enhance HUVEC proliferation, migration, and tube formation. Importantly, ME-treated HUVECs (MEXs) displayed significantly increased migration, but not proliferation or tube formation, compared with UE-treated HUVECs (UEXs). We found that the expression of a subset of migration-related microRNAs (miRNAs), including miR-210-3p, miR-376c-3p, miR-151a-5p, miR-296-5p, miR-122-5p, and miR-550a-5p, among others, were significantly increased or decreased in UEs, and this altered expression was likely correlated with the differential regulation of HUVEC migration. We also found that the mRNA expression of hepatocyte growth factor (HGF) was up-regulated in MEXs and UEXs and, moreover, that inhibiting HGF partially abolished the enhanced cell migration induced by UEs. Our results suggest that both MEs and UEs greatly enhanced endothelial cell (EC) functions and differentially regulated EC migration, which was mostly attributed to the different expression profiles of exosomal miRNA. These findings highlight the importance of exosomes in the regulation of angiogenesis during pregnancy. Exosomal miRNAs, in particular, may be of great significance for the regulation of angiogenesis in maintaining normal pregnancy.-Jia, L., Zhou, X., Huang, X., Xu, X., Jia, Y., Wu, Y., Yao, J., Wu, Y., Wang, K. Maternal and umbilical cord serum-derived exosomes enhance endothelial cell proliferation and migration.
View details for DOI 10.1096/fj.201701337RR
View details for PubMedID 29570394
Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2-ERα-GREB1 Transcriptional Axis.
2018; 78 (3): 671-684
Resistance to cancer treatment can be driven by epigenetic reprogramming of specific transcriptomes in favor of the refractory phenotypes. Here we discover that tamoxifen resistance in breast cancer is driven by a regulatory axis consisting of a master transcription factor, its cofactor, and an epigenetic regulator. The oncogenic histone methyltransferase EZH2 conferred tamoxifen resistance by silencing the expression of the estrogen receptor α (ERα) cofactor GREB1. In clinical specimens, induction of DNA methylation of a particular CpG-enriched region at the GREB1 promoter negatively correlated with GREB1 levels and cell sensitivity to endocrine agents. GREB1 also ensured proper cellular reactions to different ligands by recruiting distinct sets of ERα cofactors to cis-regulatory elements, which explains the contradictory biological effects of GREB1 on breast cancer cell growth in response to estrogen or antiestrogen. In refractory cells, EZH2-dependent repression of GREB1 triggered chromatin reallocation of ERα coregulators, converting the antiestrogen into an agonist. In clinical specimens from patients receiving adjuvant tamoxifen treatment, expression levels of EZH2 and GREB1 were correlated negatively, and taken together better predicted patient responses to endocrine therapy. Overall, our work suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program.Significance: This study suggests a new strategy to overcome endocrine resistance in metastatic breast cancer by targeting a particular epigenetic program defined within. Cancer Res; 78(3); 671-84. ©2017 AACR.
View details for DOI 10.1158/0008-5472.CAN-17-1327
View details for PubMedID 29212856
View details for PubMedCentralID PMC5967248
The nonsense-mediated RNA decay pathway is disrupted in inflammatory myofibroblastic tumors.
The Journal of clinical investigation
2016; 126 (8): 3058-62
Inflammatory myofibroblastic tumors (IMTs) are characterized by myofibroblast proliferation and an inflammatory cell infiltrate. Little is known about the molecular pathways that precipitate IMT formation. Here, we report the identification of somatic mutations in UPF1, a gene that encodes an essential component of the nonsense-mediated RNA decay (NMD) pathway, in 13 of 15 pulmonary IMT samples. The majority of mutations occurred in a specific region of UPF1 and triggered UPF1 alternative splicing. Several mRNA targets of the NMD pathway were upregulated in IMT samples, indicating that the UPF1 mutations led to reduced NMD magnitude. These upregulated NMD targets included NIK mRNA, which encodes a potent activator of NF-κB. In human lung cells, UPF1 depletion increased expression of chemokine-encoding genes in a NIK-dependent manner. Elevated chemokines and IgE class switching events were observed in IMT samples, consistent with NIK upregulation in these tumors. Together, these results support a model in which UPF1 mutations downregulate NMD, leading to NIK-dependent NF-κB induction, which contributes to the immune infiltration that is characteristic of IMTs. The molecular link between the NMD pathway and IMTs has implications for the diagnosis and treatment of these tumors.
View details for DOI 10.1172/JCI86508
View details for PubMedID 27348585
View details for PubMedCentralID PMC4966300
Effects of Human Umbilical Cord Mesenchymal Stem Cells on Human Trophoblast Cell Functions In Vitro.
Stem cells international
2016; 2016: 9156731
Trophoblast cell dysfunction is involved in many disorders during pregnancy such as preeclampsia and intrauterine growth restriction. Few treatments exist, however, that target improving trophoblast cell function. Human umbilical cord mesenchymal stem cells (hUCMSCs) are capable of self-renewing, can undergo multilineage differentiation, and have homing abilities; in addition, they have immunomodulatory effects and paracrine properties and thus are a prospective source for cell therapy. To identify whether hUCMSCs can regulate trophoblast cell functions, we treated trophoblast cells with hUCMSC supernatant or cocultured them with hUCMSCs. Both treatments remarkably enhanced the migration and invasion abilities of trophoblast cells and upregulated their proliferation ability. At a certain concentration, hUCMSCs also modulated hCG, PIGF, and sEndoglin levels in the trophoblast culture medium. Thus, hUCMSCs have a positive effect on trophoblast cellular functions, which may provide a new avenue for treatment of placenta-related diseases during pregnancy.
View details for DOI 10.1155/2016/9156731
View details for PubMedID 26949402
View details for PubMedCentralID PMC4753693
Potential involvement of placental AhR in unexplained recurrent spontaneous abortion.
Reproductive toxicology (Elmsford, N.Y.)
2016; 59: 45-52
Recurrent spontaneous abortion (RSA) is a common complication of pregnancy. Recent studies have demonstrated that the aryl hydrocarbon receptor (AhR) might play important roles in establishing and maintaining early pregnancy. In this study, we found that placental AhR protein levels were significantly lower and placental CYP1A1 mRNA levels were higher in unexplained RSA (URSA) patients than in control subjects. The results of immunohistochemical analyzes showed that placental AhR was expressed in syncytiotrophoblast cells and that the level of AhR was markedly lower in these cells in URSA subjects than in control subjects. β-Naphthoflavone (β-NF, an AhR ligand) at 5μM significantly inhibited proliferation and migration in HTR-8/SVneo cells and was associated with the activation of AhR. Moreover, overexpressing AhR in JAR cells significantly increased CYP1A1 mRNA levels and inhibited cell migration. These results indicate that AhR is highly activated in URSA placentas and that the activation of AhR in the placenta might impair trophoblast cell proliferation and migration, possibly leading to the occurrence of URSA.
View details for DOI 10.1016/j.reprotox.2015.11.005
View details for PubMedID 26593447
Endocan of the maternal placenta tissue is increased in pre-eclampsia.
International journal of clinical and experimental pathology
2015; 8 (11): 14733-40
Pre-eclampsia (PE) is associated with intravascular inflammation and endothelial dysfunction. Interestingly, endocan plays a predominant role in the vascular inflammation and is considered as a biomarker of endothelial dysfunction. The aim of this study was to explore whether the endocan levels in serum and placenta were different between pregnant women with PE and the normal pregnancies.Total 22 patients, including 10 normal pregnant women and 12 patients with PE, were included in this study. Immunohistochemistry was used to evaluate the location of endocan. Then, the mRNA and protein levels of endocan in placenta were detected using qRT-PCR and western blotting. Serum endocan concentration was measured by ELISA.Endocan protein was present in the human placenta, and the mRNA and protein levels of placenta tissues were elevated (P < 0.05) in the normal pregnancy with third trimester than those with first trimester. Furthermore, the expression of endocan mRNA and protein were increased in the placenta tissues of PE compared with in the normal pregnancy (P < 0.05); however, the endocan concentration of maternal serum did not have significant differences.Endocan may play a role in the progression of pregnancy and has a potential to be a new marker for the detective of PE.
View details for PubMedID 26823798
View details for PubMedCentralID PMC4713584
Preeclampsia does not alter vascular growth and expression of CD31 and vascular endothelial cadherin in human placentas.
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
2015; 63 (1): 22-31
Preeclampsia is characterized by maternal endothelial dysfunction (e.g., increased maternal vascular permeability caused by the disassembly of endothelial junction proteins). However, it is unclear if preeclampsia is associated with impaired vascular growth and expression of endothelial junction proteins in human placentas. Herein, we examined vascular growth in placentas from women with normal term (NT) and preeclamptic (PE) pregnancies using two endothelial junction proteins as endothelial markers: CD31 and vascular endothelial-cadherin (VE-Cad). We also compared protein and mRNA expression of CD31 and VE-Cad between NT and PE placentas, and determined the alternatively spliced expression of CD31 using PCR. We found that CD31 and VE-Cad were immunolocalized predominantly in villous endothelial cells. However, capillary number density (total capillary number per unit villous area) and capillary area density (total capillary lumen area per unit villous area) as well as CD31 and VE-Cad protein and mRNA levels were similar between NT and PE placentas. PCR in combination with sequence analysis revealed a single, full-length CD31, suggesting that there are no alternatively spliced isoform of CD31 expressed in placentas. These data indicate that preeclampsia does not significantly affect vascular growth or the expression of endothelial junction proteins in human placentas.
View details for DOI 10.1369/0022155414558063
View details for PubMedID 25362142
View details for PubMedCentralID PMC4395995
Decreased maternal serum 2-methoxyestradiol levels are associated with the development of preeclampsia.
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
2014; 34 (6): 2189-99
2-methoxyestradiol (2-ME), a natural metabolite of 17β-estradiol, is synthesized by catechol-O-methyltransferase (COMT). The aim of this study was to explore the maternal 2-ME concentration and placental COMT expression in the different trimesters of normal pregnancy and preeclamptic pregnancies, as well as the effects of 2-ME on cell proliferation and migration of HTR-8/SVneo under normoxic (20% O2) and hypoxic (2.5% O2) conditions.2-ME levels were examined by ELISA. COMT protein expression was analyzed by Western blot and immunohistochemistry. Cell proliferation and migration were measured by crystal violet assay and transwell system under either normoxia or hypoxia.Maternal 2-ME concentration was elevated with the progression of pregnancy, in contrast, 2-ME was lower in women diagnosed with mild preeclampsia (mPE; 23%) and severe preeclampsia (sPE; 32%) as compared with normotensive full term pregnancies. Meanwhile, preterm controls had lower levels of 2-ME than full term controls. Soluble cytoplasmic COMT (S-COMT), but not membrane-bound COMT (MB-COMT) levels in placentas were increased by 2.5 fold in the full term vs. the first trimester placentas. Furthermore, 2-ME suppressed cell proliferation under 20% O2 but not 2.5% O2, while 2-ME promoted cell migration under 2.5% but not 20% O2in vitro.Considering 2.5% O2 is a state more closely mimicking in vivo condition, these data suggest a decrease in 2-ME levels may inhibit trophoblast cell migration, possibly leading to PE.
View details for DOI 10.1159/000369662
View details for PubMedID 25562165
Expression of G-protein subunit α-14 is increased in human placentas from preeclamptic pregnancies.
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society
2014; 62 (5): 347-54
G-proteins mediate cellular function upon interaction with G-protein coupled receptors. Of the 16 mammalian G-protein α subunits identified, G-protein subunit α-11 (GNA11) and -14 (GNA14) have been implicated in modulating hypertension and endothelial function. However, little is known about their expression and roles in human placentas. Here, we examined GNA11 and GNA14 protein expression in first trimester (FT), normal term (NT), and severe preeclamptic (sPE) human placentas as well as in NT human umbilical cords. We found that GNA11 and GNA14 were immunolocalized primarily in trophoblasts, villous stromal cells, and endothelial cells in placentas as well as in endothelial and/or smooth muscle cells of the umbilical cord artery and vein. Western blotting revealed that the GNA14, but not GNA11, protein levels were increased (2.5-2.9 fold; p<0.01) in sPE vs. NT placentas. GNA11 protein was detected only in NT, but not FT, placentas, whereas GNA14 protein levels were increased (7.7-10.6 fold; p<0.01) in NT vs. FT placentas. Thus, GNA11 and GNA14 may mediate the function of several cell types in placentas. Moreover, the high expression of GNA14 in sPE placentas may also imply its importance in sPE pregnancies as in the other hypertension-related disorders.
View details for DOI 10.1369/0022155414521213
View details for PubMedID 24423937
View details for PubMedCentralID PMC4005364
ITE and TCDD differentially regulate the vascular remodeling of rat placenta via the activation of AhR.
2014; 9 (1): e86549
Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 µg/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 µg/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-γ (IFN-γ) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in intrauterine fetal death.
View details for DOI 10.1371/journal.pone.0086549
View details for PubMedID 24475139
View details for PubMedCentralID PMC3901702
P21 (waf1/cip1) is required for non-small cell lung cancer sensitive to Gefitinib treatment.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
2011; 65 (3): 151-6
Lung cancer is the leading cause of death from cancer in the world. Gefitinib is known to its inhibition of EGFR tyrosine kinase and worldwide used for antitumor in non-small cell lung cancer (NSCLC). Here, we show that Gefitinib reduces p-Akt levels, concomitant with elevation of p21 levels and suppression of cdk2/4 and cyclinE/D1 activities which result in impaired cell cycle progression through G1 arrest only in NSCLC cells in which it inhibits growth. We find that Gefitinib-induced p21 protein stability, rather than increased RNA accumulation, was responsible for the elevated p21 levels. More, treatment of beta-elemene, a natural plant drug extracted from Curcuma wenyujin, restored sensitivity to Gefitinib via the mechanism modulated the elevation of p21 levels in the cells which are acquired resistance to Gefitinib. These data suggest that administration of Gefitinib in combination with beta-elemene may offer great opportunities for NSCLC which are acquired resistance to Gefitinib. The p21 effect on the cells to response to Gefitinib was further confirmed by p21 over-expression and knockdown studies pointing to a requirement of p21 for the cells sensitive to Gefitinib. Thus, we propose that p21 is required for Gefitinib-sensitive NSCLC cells.
View details for DOI 10.1016/j.biopha.2011.02.009
View details for PubMedID 21616632
Combined treatment with TNF-alpha/gefitinib alleviates the resistance to gefitinib in PC-9 cells.
2009; 20 (9): 832-7
Gefitinib has been approved for the treatment of patients with non-small cell lung cancer. However, its efficiency is limited by the development of drug resistance. Additional treatments for cases of non-small cell lung cancer relapsing with treatment with gefitinib are urgently required. To investigate the mechanisms of acquired resistance to gefitinib, we established PC-9-ZD, a human lung cancer cell line resistant to gefitinib after long-term exposure to the drug. PC-9-ZD cells showed more resistance to gefitinib than their parental PC-9 cells. We show that gefitinib reduces p-Akt levels, concomitant with elevation of p21 levels and suppression of cdk2/4 and cyclinE/D1 activities, which result in impaired cell cycle progression through G1 arrest only in parental PC-9 cells, in which it inhibits growth. Our present data suggested that after long-term exposure to gefitinib, the survival of PC-9-ZD cells with heightened levels of p-Akt and reduced levels of p21 resisted further gefitinib-induced inhibition of cell growth. To explore a new strategy to improve the efficacy of gefitinib, we treated the cells with tumor necrosis factor-alpha (TNF-alpha) and found that the cells with acquired resistance to gefitinib showed increasing sensitivity to TNF-alpha, which correlated with the low activation level of nuclear factor (NF)kappaB/p65 in PC-9-ZD cells. TNF-alpha treatment induced an elevated activated NFkappaB/p65, concomitant with induced p21 levels, which resulted in increased sensitivity to gefitinib in PC-9-ZD cells. Consistent with our earlier observation that p21 is induced in an NFkappaB/p65-dependent manner, we conclude that p21 plays an important role in mediating cell growth inhibition by gefitinib. Thus, we proposed that combined treatment with TNF-alpha/gefitinib is an efficient therapeutic strategy for tumors that develop resistance to gefitinib.
View details for DOI 10.1097/CAD.0b013e32832f4b64
View details for PubMedID 19620837