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Biomedical subjects

Guiying Nie

Publications and source records attributed to Guiying Nie.

11 recordsLinked to original sources
PubMed2006

Serine proteases HTRA1 and HTRA3 are down-regulated with increasing grades of human endometrial cancer.

OBJECTIVE: The high temperature requirement factor A (HTRA) family consists of serine proteases with domains homologous to those of bacterial HTRA. Four human HTRA members have been described: HTRA1-4. HTRA1 and HTRA3 share a high degree of domain homologies and may therefore share a functional similarity. HTRA1 mRNA and protein is reported to be down-regulated in SV40-transformed cells, a malignant melanoma cell line, ovarian tumors, and ovarian cancer cell lines, suggesting a progressive loss of HTRA1 and the protein in cancer. This raises the possibility that HTRA3 may likewise be involved in cancer. This study examined the expression of mRNA and protein levels of HTRA1 and HTRA3 in human endometrial cancer (EC). METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed in normal endometrium (n = 4) and in three grades of EC (n = 5 for each EC grade). Immunohistochemistry was used to determine the protein expression and the cellular localization of HTRA1 and HTRA3 in normal endometrium tissue (n = 6) and in three grades of EC (n = 8-10 for each EC grade). RESULTS: RT-PCR analysis showed a significant reduction of HTRA1 and HTRA3 mRNA in endometrial cancer compared to normal endometrium. HTRA1 and HTRA3 protein showed a similar pattern of expression in EC tissue. Positive immunostaining, scored semiquantitatively, revealed a significant decrease of HTRA1 and 3 protein expression with increasing grades of EC. CONCLUSION: These data suggest that HTRA1 and HTRA3 mRNA and protein levels decrease with increasing grades of EC.

Aged↗
PubMed2006

Distinct expression and localization of serine protease HtrA1 in human endometrium and first-trimester placenta.

Mammalian embryos cannot survive without the placenta. Development of the human placenta requires trophoblast proliferation, differentiation, and invasion as well as highly coordinated modulation of the maternal uterus. HtrA1 is a member of the recently identified mammalian HtrA (high temperature requirement factor A) serine protease family with a high level of expression in the placenta. In this study, we examined whether HtrA1 expression (mRNA and protein) is associated with placental development in the human. HtrA1 is up-regulated in both endometrial glands and decidual cells during endometrial preparation for embryo implantation and during first-trimester pregnancy at placentation. HtrA1 expression was also detected in certain trophoblast subtypes during early pregnancy. The villous syncytiotrophoblast and cytotrophoblast showed the strongest expression while the interstitial extravillous trophoblast showed the lowest or no expression of HtrA1. The distinct distribution of HtrA1 at the maternal-trophoblast interface suggests that HtrA1 may play a role in placental development.

Decidua↗
PubMed2006

Complex expression patterns support potential roles for maternally derived activins in the establishment of pregnancy in mouse.

Maternal-fetal communications are critical for the establishment of pregnancy. Embryonic growth and differentiation factors produced by the oviduct and uterus play essential roles during the pre- and early post-implantation phases. Although several studies indicate roles for activin in embryonic development, gene-knockout studies have failed to identify a critical role in mammalian embryogenesis. We hypothesized that activin is produced by maternal tissues during the establishment of pregnancy, and thus maternally derived activin could compensate for the absence of embryonic activin in null homozygotes during critical developmental stages. We investigated the expression of inhibin alpha, activin betaA, and betaB subunits in the mouse oviduct and uterus during the estrous cycle and early pregnancy, and in the early conceptus. Inhibin alpha subunit was weakly expressed, while activin betaA and betaB subunits were strongly expressed in oviduct and uterus at estrous, and dramatically upregulated in the uterus on each day of pregnancy between days 3.5 and 8.5 post coitum. Prior to implantation, activin betaA and betaB subunits were immunolocalized to oviductal and uterine epithelial cells; following implantation they were expressed in the stroma, in a wave preceding decidualization. Later in pregnancy, activin betaA and betaB subunits were present in decidua basalis, trophoblast giant cells, and labyrinth zone of the developing placenta. Expression of activin betaA subunit was also detected in blastocysts and early post-implantation embryos. These data are consistent with a role for maternally derived activins in the support of the pre-implantation embryo, and during gastrulation and embryogenesis.

Activins↗
PubMed2005

Serine peptidase HTRA3 is closely associated with human placental development and is elevated in pregnancy serum.

HTRA3 is a newly identified serine peptidase of the mammalian HTRA (high-temperature requirement factor A) family, that is upregulated dramatically during mouse placental development. The current study determined whether HTRA3 was involved in human placentation. During the menstrual cycle, HTRA3 was expressed primarily in the endometrial glands, being significantly upregulated toward the mid- to late secretory phases; prominent expression in the stroma detected only in the decidual cells in the late secretory phase. Thus, overall endometrial HTRA3 expression was highest in the late secretory phase, when the endometrium is prepared for maternal-trophoblast interaction. During the first trimester of pregnancy, both glandular and decidual HTRA3 expression increased further with the decidual upregulation being highly significant. The strong link between HTRA3 expression and endometrial stromal cell decidualization was further established in an in vitro model using primary endometrial stromal cells. HTRA3 was also expressed by certain trophoblast subtypes in the first-trimester placenta: strongly in the villous syncytiotrophoblast, trophoblast shell, and endovascular trophoblast and weakly in the distal portion of the trophoblast cell columns but not in villous cytotrophoblast, the proximal region of the cell columns, or interstitial trophoblast. Upregulation of HTRA3 expression in association with placental development was revealed by a significant elevation of this protein in the maternal serum during the first trimester. We thus propose that HTRA3 is a previously unrecognized factor closely associated with and potentially important for human placentation. This study established crucial groundwork for future investigations toward establishing the physiological roles of HTRA3 in human placentation.

Antibody Specificity↗
PubMed2005

Serine protease HtrA1 is developmentally regulated in trophoblast and uterine decidual cells during placental formation in the mouse.

Development of a hemochorial placenta involves trophoblast proliferation, differentiation, and invasion into the uterus to promote blood flow to the embryo. Trophoblast invasion is tightly controlled by expression of specific proteases in the trophoblast and highly coordinated activities in the uterus. One uterine event essential for placentation is the developmentally regulated formation and regression of the decidua. In mice, decidual regression takes place in a temporal- and spatial-specific manner that is coordinated with placental development. In this study, we identified that the serine protease HtrA1 (high temperature requirement factor A1) was specifically expressed in differentiated trophoblast cells, especially the giant cells, during the early stages of placental development. A high level of HtrA1 expression was also detected in decidua capsularis specifically at the decidual-trophoblast interface where active involution occurs. Thus, we have identified a previously unknown role for HtrA1 as a protease potentially important for trophoblast differentiation/invasion and uterine decidual regression during placental development.

Animals↗
PubMed2005

Identification of novel endometrial targets for contraception.

Successful embryo implantation is a critical step in establishing pregnancy and requires appropriate preparation of the endometrium to provide a transient state of "uterine receptivity." The most essential of the molecular events determining receptivity may therefore provide potential targets for postcoital contraception. Using the mouse as a model, we identified molecules specifically regulated in the endometrium at very early implantation: these were monoclonal nonspecific suppressor factor beta (MNSFbeta), splicing factor SC35, a novel protease of the HtrA family, termed HtrA3, calcium-binding protein (CaBP)-d9k (calbindin d9k) and proprotein convertase 6 (PC6). All of these molecules were also expressed in human endometrium, with the exception of CaBP-d9k, which was represented by the functionally similar CaBP-d28k. Appropriate spatial and temporal expressions of mRNA and protein were demonstrated for all five candidate molecules in mouse and primate (human and rhesus monkey) endometrium during the menstrual cycle and early pregnancy. Functional studies in mice established that blocking production of the CaBPs and PC6 within the endometrium completely prevented implantation and thus provided proof of principle that these molecules are potential contraceptive targets.

Animals↗
PubMed2004

Inhibiting uterine PC6 blocks embryo implantation: an obligatory role for a proprotein convertase in fertility.

Successful embryo implantation involves complex interactions between the embryo and the uterus and is critical in establishing pregnancy. Proprotein convertase (PC) 6 (PC6) is one of the PC endoproteases regulating protein function through posttranslational activation of precursor proteins, including growth and differentiation factors. Here we show that PC6 protein is induced in the uterine stromal cells specifically at the site of embryo attachment during early pregnancy in mice. In vivo blocking of uterine production of PC6 protein using morpholino antisense oligonucleotides in mice resulted in total inhibition of implantation, revealing a vital role for PC6 in modulating the uterus for embryo implantation. Studies in primates (rhesus monkey and human) showed a dramatic upregulation of endometrial PC6 during the phase of uterine receptivity and at implantation, particularly during a critical uterine cell differentiation process termed decidualization. Thus, the current studies have demonstrated that PC6 is an essential molecule in modulating uterine function to support the establishment of embryo implantation. Interestingly, PC6 is one of the PCs identified to be important in processing the coat protein of HIV; inhibition of PCs has been suggested to be an effective approach to reduce HIV transmission. We therefore propose the novel concept that PC6 could be a potential nonhormonal target in the female reproductive tract for dual protection for women, both in preventing pregnancy and reducing HIV infection.

Animals↗
PubMed2004

Requirement for proprotein convertase 5/6 during decidualization of human endometrial stromal cells in vitro.

Decidualization of endometrial stromal cells (ESCs) is critical for embryo implantation and maintenance of pregnancy. Proprotein convertase (PC) 5/6 is suggested to play an important role in the processes of stromal cell decidualization and embryo implantation in the mouse. PC5/6 is a member of the PC family responsible for processing precursor proteins to their active forms by selective proteolysis. In this study, we investigated the regulation of PC5/6 mRNA and protein expression in human ESCs during decidualization in vitro. Real-time PCR analyses revealed a significant increase in PC5/6 mRNA levels in ESCs treated with 17 beta-estradiol (E(2)) plus medroxy-progesterone acetate during decidualization. On the other hand, E(2) alone did not increase PC5/6 mRNA expression. Intense PC5/6 immunoreactivity was observed in the cytoplasm of E(2) plus medroxy-progesterone acetate-treated ESCs (decidualized ESCs) compared with E(2)-treated ESCs on d 12 of culture (nondecidualized ESCs). This PC5/6 immunoreactivity was abolished by cotreatment with ZK 98299, a progesterone receptor antagonist. Western blotting revealed PC5/6 as approximately 120-kDa bands (pro- and mature forms) and a 65-kDa band (C-terminally truncated form) in decidualized ESCs. Using an antisense morpholino approach, prolactin production, a typical marker for decidualization, was significantly attenuated in decidualized ESCs after treatment with PC5/6 morpholino antisense oligonucleotides in comparison with controls. These results suggest that PC5/6 plays a key role for decidualization in human endometrium.

Cells, Cultured↗
PubMed2002

Presence of active gelatinases in endometrial carcinoma and correlation of matrix metalloproteinase expression with increasing tumor grade and invasion.

BACKGROUND: The actions of the extracellular-matrix degrading enzymes, matrix metalloproteinases (MMPs), are implicated in tumorigenesis. The cellular localization of MMP-2, MMP-9, membrane type 1 (MT1)-MMP, tissue inhibitors of metalloproteinases (TIMPs) 1-3, and the presence of active gelatinases were investigated in endometrial carcinoma. METHODS: Endometrial carcinomas were grouped according to histologic grade (Grades 1-3), depth of myometrial invasion (0, < 50%, > 50%) and the presence of vascular/lymphatic invasion. Twenty-nine endometrial carcinoma biopsies were investigated immunohistochemically to determine the tissue localization of MMP-2 (gelatinase A), MMP-9 (gelatinase B), MT1-MMP, and TIMPs 1-3. In situ hybridization was performed to localize MMP-2 and MMP-9 mRNA. The presence of active gelatinases was assessed using in situ zymography. RESULTS: Epithelial tumor cells were the main site of MMP-2, MMP-9, and MT1-MMP protein. Variable stromal cell localization was also observed, particularly in areas adjacent to tumor nests. Semiquantitative analysis revealed increases in MMP-9 and MMP-2 but not MT1-MMP staining scores in tumor epithelial cells in the transition from histologic Grade 1 to Grades 2 and 3. Matrix metalloproteinase-9 and MT1-MMP staining scores in tumor cells were significantly associated with the presence of myometrial invasion and vascular/lymphatic invasion, while MMP-2 did not correlate with these factors. In addition, MT1-MMP was co-localized with MMP-2, supporting its role in the activation of proMMP-2. Tumor cells from all histologic grades stained intensely for TIMP-2 and TIMP-3 proteins, while variable stromal staining was observed. In Grade 1 carcinomas TIMP-1 was predominantly immunolocalized to the stromal compartment with variable tumor cell localization being observed in Grades 2 and 3 carcinomas. Matrix metalloproteinase-9 and MMP-2 mRNAs were predominantly observed in tumor epithelial cells as well as in the stroma to varying degrees. In situ zymography revealed active forms of gelatinases at the cellular surface and in association with tumor epithelial cells within endometrial carcinoma tissues. CONCLUSIONS: These data suggest that increasing expression of MMPs and endometrial carcinoma progression are closely related. Active gelatinases are present in endometrial carcinoma, resulting in alterations to the microenvironment that promote tumor invasion and metastasis.

Biopsy↗
PubMed2002

Newly identified endometrial genes of importance for implantation.

The mammalian uterus is normally not receptive to embryo implantation except during the very limited 'window of implantation'. To identify genes that may be responsible for this phenomenon the technique of RNA differential display (DD-PCR) was applied to implantation and inter-implantation sites on day 4.5 of pregnancy in the mouse, the time at which the blastocyst becomes attached to the endometrium. Three of these genes were identified as splicing factor SC35, calbindin-D9k and monoclonal non-specific suppressor factor beta (MNSFbeta). Expression of SC35 mRNA, which is responsible for removal of introns from pre-mRNA, is much higher in implantation than in interimplantation sites during pregnancy. Expression of alternatively spliced mRNAs for SC35 is differentially regulated by early pregnancy and steroid hormones. By contrast, calbindin-D9k, a regulator of calcium, is upregulated by progesterone and its mRNA increases in the uterus during early pregnancy compared with during the cycle, although it is significantly lower in implantation sites than in interimplantation sites on days 4.5-5.5 of pregnancy, but subsequently becomes barely detectable in both sites. The mRNA for calbindin-D9k is predominantly in endometrial luminal epithelium. MNSFbeta, a cytokine involved in regulation of the immune system, showed lower expression at implantation sites than interimplantation sites on day 4.5 of pregnancy, when embryos first attach to the uterus and initiate implantation, and on day 5.5 when implantation has advanced. Immunohistochemically, the protein was localized to endometrial stromal cells in the non-pregnant uterus, but disappeared as decidualization progressed. The precise roles of these three proteins in the process of embryo implantation remains to be determined. Homologues of the proteins may contribute to the development of the 'window of implantation' in the human and hence be appropriate targets for new post-coital contraceptives or may be manipulated to improve fertility.

Animals↗