High expression of N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma

Niimi, Keiko; Yamamoto, Eiko; Fujiwara, S.; Shinjo, Keiko; Kotani, Tomomi; Umezu, Tomokazu; Kajiyama, Hiroaki; Shibata, Kiyosumi; Ino, Kazuhiko; Kikkawa, Fumitaka

doi:10.1038/bjc.2012.496

Cited by 25 publications

(27 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Failure or exacerbation of CTB invasion results in pregnancy complications. For example, shallow invasion and minimal vessel remodeling are characteristics of PE (33), whereas aggressive invasion is characteristic of placental site tumors or choriocarcinoma (34,35). Therefore, pro-and anti-invasive mechanisms function simultaneously and are delicately balanced to keep normal human placentation.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of CD81 inhibits cytotrophoblast invasion and mediates maternal endothelial cell dysfunction in preeclampsia

Shen

Diao

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Preeclampsia (PE) is initiated by abnormal placentation in the early stages of pregnancy, followed by systemic activation of endothelial cells of the maternal small arterioles in the late second or third trimester (TM) of pregnancy. During normal pregnancy, placental cytotrophoblasts (CTBs) invade the maternal uterine wall and spiral arteries, whereas this process is interrupted in PE. However, it is not known how the malformed placenta triggers maternal endothelial crisis and the associated manifestations. Here, we have focused on the association of CD81 with PE. CD81, a member of the tetraspanin superfamily, plays significant roles in cell growth, adhesion, and motility. The function of CD81 in human placentation and its association with pregnancy complications are currently unknown. In the present study, we have demonstrated that CD81 was preferentially expressed in normal first TM placentas and progressively downregulated with gestation advance. In patients with early-onset severe PE (sPE), CD81 expression was significantly up-regulated in syncytiotrophoblasts (STBs), CTBs and the cells in the villous core. In addition, high levels of CD81 were observed in the maternal sera of patients with sPE. Overexpressing CD81 in CTBs significantly decreased CTB invasion, and culturing primary human umbilical vein endothelial cells (HUVECs) in the presence of a high dose of exogenous CD81 resulted in interrupted angiogenesis and endothelial cell activation in vitro. Importantly, the phenotype of human PE was mimicked in the CD81-induced rat model.is characterized by a new onset of hypertension and proteinuria after 20 wk of gestation. Early-onset severe PE (sPE, ≤ 34 wk) is associated with a high incidence of eclampsia, cerebrovascular complications, and fetal growth restriction, which severely threaten maternal and fetal health (1). Although the etiology of PE remains elusive, this disease has two known stages: In stage I, inadequate cytotrophoblast (CTB) invasion early in the pregnancy causes abnormal placentation; in stage II, systemic endothelial cell activation and clinical manifestations occur in the second or third trimester (TM), which are associated with the release of molecules and factors from the shallowly implanted placenta (2, 3).CD81 is a widely expressed tetraspanin that provides a scaffold for signaling molecules and orchestrates interactions between membrane-associated proteins to initiate signaling cascades that regulate cell adhesion, migration, and invasion (4-7). CD81 is also a tumor suppressor that inhibits the migration and invasion of some malignant tumor cells (8, 9). In addition, an increasing number of studies have reported that CD81 is one of the main components of exosomes and can be released into maternal circulation or delivered to certain organs and tissues (10-12). Our previous study showed that CD81 is highly expressed in LPS-treated HTR-8/SV neo cells derived from human first TM extravillous trophoblast cells and induces trophoblast syncytialization (13); however, the role of CD81 in ...

show abstract

Section: Discussionmentioning

confidence: 99%

Up-regulation of CD81 inhibits cytotrophoblast invasion and mediates maternal endothelial cell dysfunction in preeclampsia

Shen

Diao

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Cell adhesion assay was performed as previously reported (20,25). Cells (4x10 4 ) were plated in 100 ml of medium in 96-well plates coated with fibronectin, collagen type I or collagen type IV (Becton-Dickinson, Franklin Lakes, NJ, uSA).…”

Section: Methodsmentioning

confidence: 99%

“…Immunohistochemical staining for GnT-IVa protein was performed using a monoclonal antiGnT-IVa antibody (sc-100785; Santa Cruz Biotechnology, Inc., Santa Cruz, CA, uSA) at a dilution of 1:400 as previously described (20,21). Immunohistochemical staining for Griffonia simplicifolia lectin-II (GSL-II) was performed by a previous method with modification (22).…”

Section: Methodsmentioning

confidence: 99%

“…Migration assay and invasion assay were performed using the Transwell inserts (Corning Inc., Corning, NY, USA) with a filter of 6.5 mm diameter and 8 µm pore size for 24-well plates as described earlier (20,21). Invasion assay was performed using the upper chambers coated with Matrigel (Collaborative Biomedical Products, Bedford, MA, uSA).…”

Section: Methodsmentioning

confidence: 99%

“…Takamatsu et al (19) confirmed the elevated activity of GnT-IV and higher expression level of GnT-IVa in choriocarcinoma cells compared to those in normal placentas, whereas the mRNA of GnT-IVb, another isoenzymatic form, was expressed at the same level in choriocarcinoma and placentas. Niimi et al (20) reported that GnT-IVa protein expression was strong in GTN (invasive mole and choriocarcinoma) and suggested that GnT-IVa might be involved in invasion of choriocarcinoma, using GnT-IVa suppression model. For further understanding of the role of GnT-IVa in choriocarcinoma, we established a choriocarcinoma cell line which overexpresses GnT-IVa and studied its target proteins for GnT-IVa glycosylation which contribute to the malignancy of choriocarcinoma.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma

et al. 2017

View full text Add to dashboard Cite

Abstract. Gestational trophoblastic neoplasia (GTN)results from the malignant transformation of placental trophoblasts which secrete human chorionic gonadotropin (hCG) as do normal placenta or hydatidiform mole. N-acetylglucosaminyltransferase IV (GnT-IV) is a glycosyltransferase which catalyses the formation of β1,4GlcNAc branches on the mannose core of N-glycans. Previous studies reported that β1,4GlcNAc branches on hCG were detected in GTN but not in normal pregnancy or hydatidiform mole. The aim of the present study was to understand the role of GnT-IVa in choriocarcinoma and find the target proteins for GnT-IVa glycosylation which contribute to the malignancy of choriocarcinoma. Immunohistochemistry showed that Griffonia simplicifolia lectin-II staining and GnT-IVa staining were intense in trophoblastic cells of invasive mole and choriocarcinoma. We established a choriocarcinoma cell line with GnT-IVa overexpression (Jar-GnT4a), and examined its malignant potential and target proteins for GnT-IVa glycosylation. GnT-IVa overexpression increased the cell migration and invasion (2.5-and 1.4-fold) as well as the ability to adhere to the extracellular matrix (ECM) components, including fibronectin and collagen type I and IV. The tumour formation potential of Jar-GnT4a in mice was significantly higher than that of control (P= 0.0407), and the cumulative survival rate of mice with Jar-GnT4a was relatively lower than those with control. Immunoprecipitation studies showed that β1,4GlcNAc branches of N-glycans on integrin β1 in choriocarcinoma cells were increased by GnT-IVa overexpression. Nano-LC/MS/MS analysis suggested that lysosome-associated membrane glycoprotein 2 (LAMP-2) was a target protein for glycosylation by GnT-IVa. The increase in β1,4GlcNAc branches on LAMP-2 by GnT-IVa overexpression was confirmed by lectin blot analysis using whole cell lysate and conditioned medium. Our results suggest that highly branched N-glycans generated by the action of GnT-IVa are present in trophoblastic cells of GTN in proportion to GnT-IVa expression level, and that GnT-IVa may contribute to the malignancy of choriocarcinoma by promoting cell adhesion, migration and invasion through glycosylation of integrin β1 and LAMP-2.

show abstract

Azurocidin is loaded into small extracellular vesicles via its N‐linked glycosylation and promotes intravasation of renal cell carcinoma cells

et al. 2021

View full text Add to dashboard Cite

Azurocidin (AZU1) is an antimicrobial protein secreted by neutrophils that acts as a chemoattractant for monocytes and macrophages and a permeabilizer of vascular endothelial cells. We previously identified AZU1 to be specifically present in extracellular vesicles (EVs) obtained from renal cell carcinoma (RCC) tissues. Here, we examined the relationship between Nlinked glycosylation and AZU1 loading into small EVs (SEVs). Inhibition of N-linked glycosylation by introducing mutations in three glycosylation sites inhibited AZU1 loading into SEVs. Furthermore, SEVs released from AZU1-wild-type cells increased the Ca 2+ concentration in endothelial cells and the endothelial permeability, whereas SEVs released from AZU1-mutant cells had no significant effect. Anti-AZU1 antibodies diminished the effect of SEVs on endothelial cell sheets. Collectively, we found that N-linked glycosylation of AZU1 directs its loading into SEVs, thereby enabling AZU1positive SEVs to function as potent permeabilizers of endothelial cells and leading to enhanced transendothelial migration of RCC cells.

show abstract

High expression of N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma

Cited by 25 publications

References 36 publications

Up-regulation of CD81 inhibits cytotrophoblast invasion and mediates maternal endothelial cell dysfunction in preeclampsia

Up-regulation of CD81 inhibits cytotrophoblast invasion and mediates maternal endothelial cell dysfunction in preeclampsia

N-acetylglucosaminyltransferase IVa promotes invasion of choriocarcinoma

Azurocidin is loaded into small extracellular vesicles via its N‐linked glycosylation and promotes intravasation of renal cell carcinoma cells

Contact Info

Product

Resources

About