Long Non-Coding RNA ZEB2-AS1 Augments Activity of Trophoblast Cells and Prevents the Development of Recurrent Spontaneous Abortion in Mice Through EZH2-Mediated CST3 Inhibition

Yu, Na; Chen, Xiaoyue; Du, Mengyang; Li, Hui; Wang, Yanqiu; Jiang, Feizhou; Bao, Shihua; He, Yongzhong

doi:10.1007/s43032-022-00857-7

Cited by 8 publications

(3 citation statements)

References 40 publications

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“…EZH2, an important catalytic enzyme of PRC2, is responsible for the methylation of H3K27 to form the histone modifications of H3K27me3, which can silence the expression of other genes [33, 34]. The role of EZH2 in RSA has recently been suggested [19, 35, 36]. Lv et al reported that the downregulation of EZH2 attenuated trophoblast invasion, which was involved in the pathogenesis of RSA [19].…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-specific protease 7 prevents recurrent spontaneous abortion by targeting enhancer of zeste homolog 2 to regulate trophoblast proliferation, apoptosis, migration, and invasion through the Wnt/β-catenin pathway

Zhou

Gao

et al. 2023

Biology of Reproduction

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Trophoblasts are significant components of the placenta and play crucial roles in maternal-fetal crosstalk. Adequate trophoblast migration and invasion are essential for embryo implantation and healthy pregnancy. Ubiquitin-specific protease 7 (USP7), a member of the deubiquitinating enzyme family, regulates the processes of migration and invasion in multiple tumor cells. However, the effects of USP7 on trophoblasts and its possible mechanism in the development of recurrent spontaneous abortion (RSA) are still unclear. In this study, we analyzed the expression of USP7 in villous tissues obtained from RSA patients and healthy controls, and then GNE-6776 (a USP7-specific inhibitor) and USP7 siRNA were used in a trophoblast cell line, HTR-8/SVneo, to further assess the effect of USP7 on the biological function of trophoblasts. Our results provide convincing evidence that USP7 is downregulated in the placental villous tissues of RSA patients. USP7 was found to have a crucial role in the proliferation, apoptosis, migration, invasion, and epithelial-mesenchymal transition (EMT) process of trophoblast cells. Further experiments revealed that USP7 directly interacted with the enhancer of zeste homolog 2 (EZH2) and regulated the Wnt/β-catenin signaling pathway in trophoblasts. Taken together, these findings indicate the vital role of USP7 in regulating trophoblast proliferation, migration and invasion, thus affecting the pathogenesis of RSA, providing new insights into the important role of USP7 in the maternal-fetal interface.

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Section: Discussionmentioning

confidence: 99%

Ubiquitin-specific protease 7 prevents recurrent spontaneous abortion by targeting enhancer of zeste homolog 2 to regulate trophoblast proliferation, apoptosis, migration, and invasion through the Wnt/β-catenin pathway

Zhou

Gao

et al. 2023

Biology of Reproduction

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“…ZEB2-AS1 [ 43 , 44 ] and GNG12 [ 45 ] can regulate cell proliferation, apoptosis, and migration processes and thus promote tumor cell growth of by affecting various pathways such as phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), Wnt/β-catenin, etc. However, they have not been adequately investigated in the context of follicle growth, and the lonely study has confirmed that ZEB2-AS1 could enhance the activity of trophoblast cells and prevents the development of recurrent spontaneous abortion [ 46 ]. In the present study, we observed lncRNA GNG12 and ZEB2-AS1 expression was downregulated in the OGCs from DOR patients, suggesting it may contribute to DOR development by increasing apoptosis and inhibiting cell proliferation in OGCs.…”

Section: Discussionmentioning

confidence: 99%

Expression of long noncoding RNAs in the ovarian granulosa cells of women with diminished ovarian reserve using high-throughput sequencing

et al. 2022

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Background Infertility is a global reproductive-health problem, and diminished ovarian reserve (DOR) is one of the common causes of female infertility. Long noncoding RNAs (lncRNAs) are crucial regulators of numerous physiological and pathological processes in humans. However, whether lncRNAs are involved in the development of DOR remains to be elucidated. Methods Ovarian granulosa cells (OGCs) extracted from infertile women with DOR and from women with normal ovarian reserve (NOR) were subjected to high-throughput sequencing. Comprehensive bioinformatics analysis was conducted to identify the differential expression of messenger RNAs (mRNAs) and lncRNAs. Sequencing results were validated by the selection of lncRNAs and mRNAs using real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results Compared with the NOR group, a total of 244 lncRNAs were upregulated (53 known and 191 novel), and 222 lncRNAs were downregulated (36 known and 186 novel) in the DOR group. Similarly, 457 mRNAs had differential expression between the two groups. Of these, 169 were upregulated and 288 were downregulated. Bioinformatics analysis revealed that the differentially expressed genes of mRNA and lncRNAs were considerably enriched in “cell adhesion and apoptosis”, “steroid biosynthesis”, and “immune system”. A co-expression network comprising lncRNAs and their predicted target genes revealed the possible involvement of the “thyroid hormone signaling pathway” and “protein binding, digestion and absorption” in DOR pathogenesis. The expression of SLC16A10 was positively regulated by multiple lncRNAs. After RT-qPCR validation of seven differentially expressed lncRNAs and mRNAs, respectively, the expression of lncRNA NEAT1, GNG12, ZEB2-AS1, and mRNA FN1, HAS3, RGS4, SUOX were in accordance with RNA-sequencing. Conclusions We presented the first data showing that the expression profiles of lncRNA and mRNA in OGCs between NOR and DOR patients using RNA sequencing. The lncRNAs and mRNAs that we identified may serve as novel diagnostic biomarkers for patients with DOR.

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“…Cysteine proteinase inhibitor 1 (CST1) is a secreted protein belonging to the cysteine proteinase inhibitor (CST) type 2 subfamily [20][21][22][23] . Aberrant CST1 expression has been reported to be associated with the development of some malignancies, such as breast, lung, liver and gastric cancers [24][25][26][27][28] .…”

Section: Introductionmentioning

confidence: 99%

CST1 promotes the metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer

Zhang

Chen

Wang

et al. 2023

Preprint

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Cysteine Protease Inhibitor 1 (CST1), a cystatin superfamily protein with the effect on the inhibition of cysteine protease activity , is reported to be involved in the development of many malignancies. Mitochondrial oxidative phosphorylation (OXPHOS) also plays an important role on regulating cancer cell growth. However, the relationship and role of CST1 and OXPHOS on esophageal squamous cell carcinoma (ESCC) remains unknown. In our pilot study, CST1 was shown the potential of promoting ESCC migration and invasion by the activation of MEK/ERK pathway. Especially mentioned, we found that CST1 is closely associated with OXPHOS by the analysis of transcriptome sequencing. And then, based on real-time ATP rate assay, mitochondrial complex I enzyme activity assay, immunofluorescence (IF), co-immunoprecipitation (CO-IP), and additions of OXPHOS inhibitor Rotenone and MEK/ERK inhibitor PD98059, we defined the effect of CST1 on mitochondrial complex I enzyme activity by interacting with GRIM19 protein to elevate OXPHOS levels, and the reciprocal regulatory relationship existed between OXPHOS and MEK/ERK pathway in ESCC cells. Finally, a study in vivo well demonstrated the potential of CST1 on ESCC metastasis by the regulation of OXPHOS and MEK/ERK pathway. This study is the first to unveil the oncogenic role of CST1 on ESCC development by enhancing mitochondrial respiratory chain complex I activity to activate an OXPHOS/MEK/ERK axis, and then promote ESCC metastasis, suggesting that CST1/OXPHOS might be a promising target for ESCC treatment.

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Long Non-Coding RNA ZEB2-AS1 Augments Activity of Trophoblast Cells and Prevents the Development of Recurrent Spontaneous Abortion in Mice Through EZH2-Mediated CST3 Inhibition

Cited by 8 publications

References 40 publications

Ubiquitin-specific protease 7 prevents recurrent spontaneous abortion by targeting enhancer of zeste homolog 2 to regulate trophoblast proliferation, apoptosis, migration, and invasion through the Wnt/β-catenin pathway

Ubiquitin-specific protease 7 prevents recurrent spontaneous abortion by targeting enhancer of zeste homolog 2 to regulate trophoblast proliferation, apoptosis, migration, and invasion through the Wnt/β-catenin pathway

Expression of long noncoding RNAs in the ovarian granulosa cells of women with diminished ovarian reserve using high-throughput sequencing

CST1 promotes the metastasis by mediating an oxidative phosphorylation/MEK/ERK axis in esophageal squamous carcinoma cancer

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