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Endometrial gene expression profiling of recurrent implantation failure after in vitro fertilization

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Abstract

Recurrent implantation failure (RIF) is diagnosed when good-quality embryos repeatedly fail to implant after transfer in several in vitro fertilization (IVF) treatment cycles. Different expression profiles in maternal mRNAs could be referring to many diseases including RIF. This study aimed to reveal significantly dysregulated selected genes expression between healthy fertile women and RIF patients in the implantation window days of the natural menstrual cycle. MME, WWC1, TNC, and FOXP3 genes were chosen as target genes regarding their possible relations with the implantation process. Pathways with these genes were identified and the relationship between these pathways and RIF was investigated. In this study, the endometrial biopsy samples were collected in the secretory phase (cycle day 20–24) of the menstrual cycle from RIF patients (n = 34) and healthy fertile controls (n = 34). After “Pathway and network-oriented GWAS analysis” (PANOGA) and “Kyoto Encyclopedia of Genes and Genomes” (KEGG) pathway analysis; “Membrane Metalloendopeptidase” (MME), “WW and C2 Domain Containing 1” (WWC1), “Tenascin C” (TNC) and “Forkhead Box P3” (FOXP3) genes were chosen as target genes by regarding their possible relation with implantation process. Detection of differences in mRNA expressions between the control group and RIF patients has been performed with the droplet digital PCR (ddPCR) method. Results of the study showed that MME and WWC1 genes expression levels are significantly (p < 0,05) up-regulated 4.9 and 5.2 times respectively and TNC gene expression level is significantly (p < 0,05) down-regulated 9 times in the RIF samples compared to the control group. However, no statistically significant difference was observed between the patient group and the control group in the expression of the FOXP3 gene (p < 0.05). Changes are observed in the expression of the renin-angiotensin system pathway in which the MME gene is involved in the implantation process. The increase in MME gene expression can be speculated to cause implantation failure by restricting the invasion of trophoblast cells. Increasing WWC1 gene expression in the Hippo signaling pathway inhibits “Yes-associated protein 1” (YAP) expression, which is a transcriptional cofactor. Inhibition of YAP protein expression may impair the implantation process by causing the failure of endometrial decidualization. The TNC gene is located in the focal adhesion pathway and this pathway reduces cell adhesion on the endometrial surface to facilitate the attachment of the embryo to the endometrium. The reason for implantation failure might be that the intercellular connections are not suitable for implantation as a result of decreased expression of the focal adhesion pathway in which the TNC gene is effective. Considering the relations between the pathways of the target genes and the implantation process, changes in the expression of target genes might be a cause of RIF.

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Data availability

All analyzed and generated data in the study are included in this paper. The clinical datasets are not publicly available regarding ethical responsibility to respect participants’ privacy rights.

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Funding

This study was supported by the Istanbul University Scientific Research Projects Department (Grant No. 32431).

Author information

Authors and Affiliations

  1. Molecular Biology and Genetics Department, Faculty of Science, Istanbul University, 34134, Istanbul, Fatih, Turkey

    İrem Gülfem Albayrak, Ezgi Nur Çolak & Tuba Günel

  2. Molecular Biology and Genetics Department, Faculty of Engineering and Natural Sciences, Uskudar University, 34662, Istanbul, Uskudar, Turkey

    İrem Gülfem Albayrak

  3. Department of Molecular Medicine, Faculty of Medicine, Istanbul University, 34093, Istanbul, Çapa, Turkey

    Fatemeh Azhari

  4. Department of Obstetrics and Gynaecology, Faculty of Medicine, Istanbul University, 34093, Istanbul, Çapa, Turkey

    Burçin Karamustafaoğlu Balcı

  5. Department of Biostatistics and Medical Informatics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Atasehir, Turkey

    Ege Ülgen & Uğur Sezerman

  6. Department of Obstetrics and Gynaecology, Acibadem Fulya Hospital, 34349, Istanbul, Beşiktaş, Turkey

    Ercan Baştu

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  1. İrem Gülfem Albayrak
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Contributions

BKB and EB contributed to patient selection and collecting samples. EÜ and US contributed to the target gene selection part. TG designed the molecular genetics experiments. İGA, FA, and ENÇ performed the RNA isolation and ddPCR. İGA performed data analysis. Each author participated in manuscript editing. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Tuba Günel.

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The authors declare no conflict of interest.

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The study was approved by the Ethical Committee of Istanbul Medical Faculty (Istanbul, Turkey; Project No: 2018/1373).

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All the study participants provided written informed consent.

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Albayrak, İ.G., Azhari, F., Çolak, E.N. et al. Endometrial gene expression profiling of recurrent implantation failure after in vitro fertilization. Mol Biol Rep 48, 5075–5082 (2021). https://doi.org/10.1007/s11033-021-06502-x

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  • DOI: https://doi.org/10.1007/s11033-021-06502-x

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