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Endometrial MicroRNA Signature during the Window of Implantation Changed in Patients with Repeated Implantation Failure.

ABSTRACT: At present, a diagnostic tool with high specificity for impaired endometrial receptivity, which may lead to implantation failure, remains to be developed. We aimed to assess the different endometrial microRNA (miRNA) signatures for impaired endometrial receptivity by microarray analysis.A total of 12 repeated implantation failure (RIF) patients and 10 infertile patients, who conceived and delivered after one embryo transfer attempt, were recruited as RIF and control groups, respectively. Endometrial specimens from the window of implantation (WOI) were collected from these two groups. MiRNA microarray was conducted on seven and five samples from the RIF and control groups, respectively. Comparative, functional, and network analyses were performed for the microarray results. Quantitative real-time polymerase chain reaction (PCR) was performed on other samples to validate the expression of specific miRNAs.Compared with those in the control group, the expression levels of 105 miRNAs in the RIF group were found to be significantly up- or down-regulated (at least 2-fold) by microarray analysis. The most relevant miRNA functional sets of these dysregulated miRNAs were miR-30 family, human embryonic stem cell regulation, epithelial-mesenchymal transition, and miRNA tumor suppressors by tool for annotations of microRNA analysis. Network regulatory analysis found 176 miRNA-mRNA interactions, and the top 3 core miRNAs were has-miR-4668-5p, has-miR-429, and has-miR-5088. Expression levels of the 18 selected miRNAs in new samples by real-time PCR were found to be regulated with the same trend, as the result of microarray analysis.There is a significant different expression of certain miRNAs in the WOI endometrium for RIF patients. These miRNAs may contribute to impaired endometrial receptivity.

SUBMITTER: Shi C

PROVIDER: S-EPMC5339930 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Endometrial MicroRNA Signature during the Window of Implantation Changed in Patients with Repeated Implantation Failure.

Shi Cheng C Shen Huan H Fan Li-Juan LJ Guan Jing J Zheng Xin-Bang XB Chen Xi X Liang Rong R Zhang Xiao-Wei XW Cui Qing-Hua QH Sun Kun-Kun KK Zhao Zhu-Ran ZR Han Hong-Jing HJ

Chinese medical journal 20170301 5

<h4>Background</h4>At present, a diagnostic tool with high specificity for impaired endometrial receptivity, which may lead to implantation failure, remains to be developed. We aimed to assess the different endometrial microRNA (miRNA) signatures for impaired endometrial receptivity by microarray analysis.<h4>Methods</h4>A total of 12 repeated implantation failure (RIF) patients and 10 infertile patients, who conceived and delivered after one embryo transfer attempt, were recruited as RIF and co ...[more]

PMID: 28229988

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Project description:IntroductionSuccessful embryo implantation, is the initiating step of pregnancy, relies on not only the high quality of the embryo but also the synergistic development of a healthy endometrium. Characterization and identification of biomarkers for the receptive endometrium is an effective method for increasing the probability of successful embryo implantation.MethodsEndometrial tissues from 22 women with a history of recurrent implantation failure (RIF) and 19 fertile controls were collected using biopsy catheters on 7-9 days after the peak of luteinizing hormone. Differentially expressed proteins (DEPs) were identified in six patients with RIF and six fertile controls using isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomics analysis.ResultsTwo hundred and sixty-three DEPs, including proteins with multiple bioactivities, such as protein translation, mitochondrial function, oxidoreductase activity, fatty acid and amino acid metabolism, were identified from iTRAQ. Four potential biomarkers for receptive endometrium named tubulin polymerization-promoting protein family member 3 TPPP3, S100 Calcium Binding Protein A13 (S100A13), 17b-hydroxysteroid dehydrogenase 2 (HSD17B2), and alpha-2-glycoprotein 1, zinc binding (AZGP1) were further verified using ProteinSimple Wes and immunohistochemical staining in all included samples (n=22 for RIF and n=19 for controls). Of the four proteins, the protein levels of TPPP3 and HSD17B2 were significantly downregulated in the endometrium of patients with RIF.DiscussionPoor endometrial receptivity is considered the main reason for the decrease in pregnancy success rates in patients suffering from RIF. iTRAQ techniques based on isotope markers can identify and quantify low abundance proteomics, and may be suitable for identifying differentially expressed proteins in RIF. This study provides novel evidence that TPPP3 and HSD17B2 may be effective targets for the diagnosis and treatment of non-receptive endometrium and RIF.

Project description:BackgroundMicroRNAs (miRNAs) are small, non-coding RNAs that are dysregulated in many diseases and can act as biomarkers. Although well-studied in cancer, the role of miRNAs in embryo implantation is poorly understood. Approximately 70% of embryos fail to implant following in-vitro fertilization and embryo transfer, 10% of patients experienced recurrent implantation failure. However, there are no well-established biomarkers that can predict implantation failure. Our purpose is to investigate distinct miRNA profiles in plasma and plasma exosomes during the window of implantation between patients with failed implantation and successful implantation.MethodsWe select a nested case-control population of 12 patients with implantation failure or successfully clinical pregnancy using propensity score matching. RNA was extracted from plasma and plasma exosomes collected during the window of implantation (WOI). MicroRNA expression in all samples was quantified using microRNA sequencing. The intersection of differently expressed miRNAs in plasma and exosomes were further validated in the GEO dataset. Significantly altered microRNAs in both plasma and plasma exosomes were then subjected to target prediction and KEGG pathway enrichment analyses to search for key signaling pathways. WGCNA analysis was performed to identify hub miRNAs associated with implantation.Results13 miRNAs were differentially expressed in both plasma and plasma exosomes in patients with implantation failure. Among them, miR-150-5p, miR-150-3p, miR-149-5p, and miR-146b-3p had consistent direction changes in endometrium of patients with recurrent implantation failure (RIF), miR-342-3p had consistent direction changes in blood samples of patients with RIF. Pathway enrichment analysis showed that the target genes of differentially expressed miRNAs are enriched in pathways related to embryo implantation. WGCNA analysis indicated that miR-150-5p, miR-150-3p, miR-146b-3p, and miR-342-3p are hub miRNAs.ConclusionsImplantation failure is associated with distinct miRNA profiles in plasma and plasma exosomes during WOI.

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:BackgroundThe molecular mechanisms underlying window of implantation (WOI) displacement in patients with recurrent implantation failure (RIF) remain unclear. This study aims to explore the transcriptomic signatures of endometrium with normal and displaced WOIs and to identify the causes of endometrial receptivity (ER) abnormalities and WOI displacement in RIF patients.MethodsIn this study, 40 RIF patients were recruited and underwent personalized embryo transfer (pET) guided by the predicted results of endometrial receptivity diagnosis (ERD) model. Transcriptome analysis of endometrium from patients with clinical pregnancies after pET was performed to identify differentially expressed genes (DEGs) associated with WOI displacement. Gene expression data from HRT and natural cycle endometrium were compared to identify specific gene expression patterns of ER-related genes during WOI.ResultsThe ERD results indicated that 67.5% of RIF patients (27/40) were non-receptive in the conventional WOI (P+5) of the HRT cycle. The clinical pregnancy rate in RIF patients improved to 65% (26/40) after ERD-guided pET, indicating the effectiveness of transcriptome-based WOI prediction. Among the 26 patients with clinical pregnancy, the gene expression profiles of P+5 endometrium from advanced (n=6), normal (n=10) and delayed (n=10) WOI groups were significantly different from each other. Furthermore, 10 DEGs identified among P+5 endometrium of 3 groups were involved in immunomodulation, transmembrane transport and tissue regeneration, which could accurately classify the endometrium with different WOIs. Additionally, a large number of ER-related genes showed significant correlation and similar gene expression patterns in P+3, P+5, and P+7 endometrium from HRT cycles and LH+5, LH+7, and LH+9 endometrium from natural cycles.ConclusionOur study shows that ER-related genes share similar gene expression patterns during WOI in both natural and HRT cycles, and their aberrant expression is associated with WOI displacements. The improvement of pregnancy outcomes in RIF patients by adjusting ET timing according to ERD results demonstrates the importance of transcriptome-based endometrial receptivity assessment and the clinical efficiency of ERD model.

Dataset Information

Endometrial MicroRNA Signature during the Window of Implantation Changed in Patients with Repeated Implantation Failure.

Publications

Endometrial MicroRNA Signature during the Window of Implantation Changed in Patients with Repeated Implantation Failure.

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