Construction of circRNA-miRNA-mRNA network in the pathogenesis of recurrent implantation failure using integrated bioinformatics study

Abstract

This research attempted to elucidate the molecular components are involved in the pathogenesis of recurrent implantation failure (RIF). We initially identified that 386 mRNAs, 144 miRNAs and 2548 circRNAs were differentially expressed (DE) in RIF and then investigated the genetic cause of the observed abnormal expression by constructing a circRNA-miRNA-mRNA network considering the competing endogenous RNA theory. We further analysed the upstream transcription factors and related kinases of DEmRNAs (DEMs) and demonstrated that SUZ12, AR, TP63, NANOG, and TCF3 were the top five TFs binding to these DEMs. Besides, protein-protein interaction analysis disclosed that ACTB, CXCL10, PTGS2, CXCL12, GNG4, AGT, CXCL11, SST, PENK, and FOXM1 were the top 10 hub genes in the acquired network. Finally, we performed the functional enrichment analysis and found that arrhythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), pathways in cancer, TNF signalling pathway and steroid hormone biosynthesis were the potentially disrupted pathways in RIF patients. Optimistically, our findings may deepen our apprehensions about the underlying molecular and biological causes of RIF and provide vital clues for future laboratory and clinical experiments that will ultimately bring a better outcome for patients with RIF.

Keywords: GEO; KEGG; bioinformatic; circular RNA; endometrium; expression; immune; implantation failure; microRNA; protein-protein interaction.

FIGURE 1

Volcano plot shows the DEMs in GSE111974(A), DEMIs in GSE71332(B) and DECs in GSE147442(C). DEMs: differentially expressed mRNAs; DEMIs: differentially expressed miRNAs [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

The CeRNA network of circRNA‐miRNA‐mRNA interactions in recurrent implantation failure. V shape indicates circRNAs, triangle indicates miRNAs and round rectangle indicates mRNAs. CeRNA: competitive endogenous RNA [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

The TFs, mediatory protein and PKs networks. Expression2Kinases investigations signified the most enriched TFs, mediatory protein and kinase from the 386 DEMs in GSE111974 according to the integrated score (p‐value and z‐score). TFs, transpiration factors; PKs, protein kinases; DEMs, differentially expressed mRNAs [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

The PPIs networks. The PPIs of 386 DEMs in GSE111974 were established using the STRING database. DEMs, differentially expressed mRNAs; PPI, protein‐protein interaction [Colour figure can be viewed at wileyonlinelibrary.com]

FIGURE 5

The functional enrichment analysis of 386 DEMs in GSE111974. The top 10 enriched GO (A) BP, (B) CC, (C) MF terms and (D) KEGG pathways. DEMs, differentially expressed mRNAs; GO, gene ontology; KEGG, Kyoto encyclopedia of genes and genomes; BP, biological process; CC, cellular component; MF, molecular function [Colour figure can be viewed at wileyonlinelibrary.com]