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Screening and identification of endometrial proteins as novel potential biomarkers for repeated implantation failure.

ABSTRACT: Inadequate endometrial receptivity may be responsible for the low implantation rate of transferred embryos in in vitro fertilization (IVF) treatments. Patients with repeated implantation failure (RIF) impact the clinical pregnancy rate for IVF. We collected endometrial tissue during the implantation window of hysteroscopy biopsies from September 2016 to December 2019 and clinical data were collected simultaneously. Patients were divided into RIF and pregnant controls group according to pregnancy outcomes. A total of 82 differentially expressed endometrial proteins were identified, including 55 up-regulated proteins (>1.50-fold, P < 0.05) and 27 down-regulated proteins (<0.67-fold, P < 0.05) by iTRAQ labeling coupled with the 2D LC MS/MS technique in the RIF group. String analysis found interactions between these proteins which assembled in two bunches: ribosomal proteins and blood homeostasis proteins. The most significant enriched Gene Ontology terms were negative regulation of hydrolase activity, blood microparticle, and enzyme inhibitor activity. Our results emphasized the corticosteroid-binding globulin and fetuin-A as the specific proteins of endometrial receptivity by Western-blot. Our study provided experimental data to establish the objective indicator of endometrial receptivity, and also provided new insight into the pathogenesis of RIF.

SUBMITTER: Wang C

PROVIDER: S-EPMC7958897 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundWindow of implantation (WOI) displacement is one of the endometrial origins of embryo implantation failure, especially repeated implantation failure (RIF). An accurate prediction tool for endometrial receptivity (ER) is extraordinarily needed to precisely guide successful embryo implantation. We aimed to establish an RNA-Seq-based endometrial receptivity test (rsERT) tool using transcriptomic biomarkers and to evaluate the benefit of personalized embryo transfer (pET) guided by this tool in patients with RIF.MethodsThis was a two-phase strategy comprising tool establishment with retrospective data and benefit evaluation with a prospective, nonrandomized controlled trial. In the first phase, rsERT was established by sequencing and analyzing the RNA of endometrial tissues from 50 IVF patients with normal WOI timing. In the second phase, 142 patients with RIF were recruited and grouped by patient self-selection (experimental group, n = 56; control group, n = 86). pET guided by rsERT was performed in the experimental group and conventional ET in the control group.ResultsThe rsERT, comprising 175 biomarker genes, showed an average accuracy of 98.4% by using tenfold cross-validation. The intrauterine pregnancy rate (IPR) of the experimental group (50.0%) was significantly improved compared to that (23.7%) of the control group (RR, 2.107; 95% CI 1.159 to 3.830; P = 0.017) when transferring day-3 embryos. Although not significantly different, the IPR of the experimental group (63.6%) was still 20 percentage points higher than that (40.7%) of the control group (RR, 1.562; 95% CI 0.898 to 2.718; P = 0.111) when transferring blastocysts.ConclusionsThe rsERT was developed to accurately predict the WOI period and significantly improve the pregnancy outcomes of patients with RIF, indicating the clinical potential of rsERT-guided pET. Trial registration Chinese Clinical Trial Registry: ChiCTR-DDD-17013375. Registered 14 November 2017, http://www.chictr.org.cn/index.aspx.

Project description:Insufficient endometrial receptivity is a major factor leading to implantation failure (IF), and the traditional way of morphological observation of endometrium cannot determine the condition of receptivity sufficiently. Considering that long-noncoding RNAs (lncRNAs) regulate endometrial receptivity and competing endogenous RNA (ceRNA) mechanism works in plenty of biological processes, ceRNA is likely to function in the pathology of IF. In the present study, we aim to construct an implantation failure related lncRNA-mRNA network (IFLMN), and to identify the key lncRNAs as the candidates for predicting endometrial receptivity. The global background network was constructed based on the presumed lncRNA-miRNA and miRNA-mRNA pairs obtained from lncRNASNP and miRTarBase. Differentially expressed genes (DEGs) of IF were calculated using the data of GSE26787, and then re-annotated as differentially expressed mRNAs (DEMs) and lncRNAs (DELs). IFLMN was constructed by hypergeometric test, including 255 lncRNA-mRNA pairs, 10 lncRNAs, and 212 mRNAs. Topological analysis determined the key lncRNAs with the highest centroid. Functional enrichment analyses were performed by unsupervised clustering, GO classification, KEGG pathway, and co-expression module analyses, achieving six key lncRNAs and their ceRNA sub-networks, which were involved in immunological activity, growth factor binding, vascular proliferation, apoptosis, and steroid biosynthesis in uterus and prepared endometrium for embryo implantation. Sixteen endometrial samples were collected during mid-luteal phase, including 8 recurrent implantation failure (RIF) or recurrent miscarriage (RM) women and 8 controls who conceived successfully. Quantitative real-time PCR was performed to compare the expression of the above six lncRNAs, which validated that the expression of all these lncRNAs was significantly elevated in endometrium of RIF/RM patients. Further studies are needed to investigate the underlying mechanism, and the lncRNAs may be developed into predictive biomarkers for endometrial receptivity.

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Screening and identification of endometrial proteins as novel potential biomarkers for repeated implantation failure.

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