Endometriosis-related CeRNA Network To Identify Predictive Biomarkers Of Endometrial Receptivity

AIMAs RNA,which plays a role in the regulation of endometrial receptivity,can be modu-lated via ceRNA mechanisms,we constructed a ceRNA network.The expression of pinopodes and immumohistochemical staining was observed to explore potential RNA/ceRNA biomarkers indicating endometrial receptivity associated with endometrio-sis.MATERIALS&METHODSA total of 16 female infertile patients were enrolled in this study.Informed consent was obtained in accordance with the institutional guidelines.All subjects were nor-mo-ovulatory with regular menstrual cycles(between 21 and35 days),between the ages of 28 and 37,and had not received hormonal treatments such as gonadotropin-releasing hormone agonists or sex steroids within 3 months of endometrial sampling.RNA se-quencing was performed on eutopic endometrium from 16 patients with and without en-dometriosis.Bioinformatics algorithms were used to predict ceRNA network and path-way analysis.The expression of pinopodes and immumohistochemical staining was ob-served.RESULTSA total of 767 mRNAs(181 up-and 586 down-regulated),231 lncRNAs(99 up-and 132 down-regulated)and 45 miRNAs(11 up-and 34 down-regulated)were detected to be differentially expressed in healthy subjects compared with those with endometriosis.Based on the ceRNA theory,we reconstructed a IncRNA-miRNA-mRNA network,which for the first time enables an overall view and analysis of the IncRNA-associated ceRNA-mediated genes related to the endometriosis receptivity of endometriosis at a system-wide level,involving 45 pathways.Overall,12 genes existed simultaneously on all three top 25 lists after the topological analysis of the fold change between the groups for IncRNAs,miRNAs and mRNAs from which ceRNA reconstruction identified 26 miRNAs,30 mRNAs,32 lncRNAs and 119 edges in the network.Decidualization and ovarian steroidogenesis,along with VEGF and TNF signaling pathways enriched in the sub-ceRNA network might be associated with endometrial receptivity in patients with endometriosis.Further selection of the IncRNAs,miRNAs and mRNAs included in the ceRNA using Pearson correlation analysis identified two co-expression modules:Module 1,for which GO classification obtained 136 enriched GO terms and KEGG analysis found three enriched KEGG pathways,and Module 2,with 121 enriched GO terms and 12 enriched KEGG pathways.The JAK-STAT signaling pathway,decidualization,oxi-doreductase activity might be involved in the impairment of endometrial receptivity in endometriosis.Our findings identified hsa-miR-449c-5p,hsa-miR-449a,DRAIC and LOC400867 as candidate biomarkers for predicting endometrial receptivity in endome-triosis.Patients with endometriosis presented lower levels of progesterone receptor type B expression.CONCLUSIONSWe demonstrated that a total of 767 mRNAs,231 lncRNAs and 45 miRNAs were de-tected to be differentially expressed in the normal group compared with the endometrio-sis group.Our findings identified hsa-miR-449c-5p,hsa-miR-449a,DRAIC and LOC400867 as the candidates for predicting endometrial receptivity.Furthermore,pa-tients with endometriosis presented with lower levels of epithelial endometrial expression of PR-B receptors,which may be associated with the impaired endometrial receptivity in patients with endometriosis.We demonstrated that a total of 767 mRNAs,231 lncRNAs and 45 miRNAs were detected to be differentially expressed in the normal group com-pared with the endometriosis group.