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. 2021 Feb 20;13(4):6076-6090.
doi: 10.18632/aging.202590. Epub 2021 Feb 20.

Hsa_circ_0038383-mediated competitive endogenous RNA network in recurrent implantation failure

Huishan Zhao  1 , Lili Chen  1 , Yinghua Shan  1 , Gang Chen  2 , Yongli Chu  3 , Huangguan Dai  1 , Xuemei Liu  1 , Hongchu Bao  1
Affiliations

Hsa_circ_0038383-mediated competitive endogenous RNA network in recurrent implantation failure

Huishan Zhao et al. Aging (Albany NY). .

Abstract

Background: Inadequate endometrial receptivity contributes to recurrent implantation failure (RIF) during IVF-embryo transfer. Though multiple circRNAs have been confirmed differentially expression in RIF, the potential function of novel circRNAs needed to be detected.

Results: The top ten DEcircRNAs were selected as initial candidates. A ceRNA network was conducted on the basis of circRNA-miRNA-mRNA potential interaction, consisting of 10 DEcircRNAs, 28 DEmiRNAs and 59 DEmRNAs. Three down-regulation circRNAs with high degree of connectivity were verified by RT-qPCR, and results suggested that only hsa_circ_0038383 was significantly downregulation in RIF compared with control group. Subsequently, three hub genes (HOXA3, HOXA9 and PBX1) were identified as hub genes. Ultimately, a subnetwork was determined based on one DEcircRNA (hsa_circ_0038383), two DEmiRNAs (has-miR-196b-5p and has-miR-424-5p), and three DEmRNAs (HOXA3, HOXA9 and PBX1). Following verification, hsa_circ_0038383/miR-196b-5p/HOXA9 axis may be a key pathway in affecting RIF.

Conclusion: In summary, a hsa_circ_0038383-mediated ceRNA network related to RIF was proposed. This network provided new insight into exploring potential biomarkers for diagnosis and clinical treatment of RIF.

Methods: We retrieved the expression profiles of RIF from GEO databases (circRNA, microRNA and mRNA) and constructed a competing endogenous RNAs (ceRNA) network based on predicted circRNA-miRNA and miRNA-mRNA pairs. The expression levels of three hub DEcircRNAs identified by cytoscape were validated by RT-qPCR.

Keywords: ceRNA; circRNA; endometrial receptivity; miRNA; recurrent implantation failure.

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Conflict of interest statement

CONFLICTS OF INTEREST: The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Flow chart of the ceRNA network analysis.
Figure 2
Figure 2
Differentially expressed circRNAs in RIF patients compared the control group. (A) Heatmap of the differentially expressed circRNAs in RIF based on GSE147442. (B) Volcano map for all circRNAs in GSE147442.
Figure 3
Figure 3
Identification of differentially expressed miRNAs. (A) Heatmap of the differentially expressed miRNAs from the GEO microarray GSE71332. (B) Volcano map for all miRNAs in GSE71332. (C, D) Overlapping between circRNA-related target miRNAs predicted by online tool and DEmiRNAs in GSE71332.
Figure 4
Figure 4
Identification of differentially expressed mRNAs. (A) Heatmap of the differentially expressed mRNAs in GSE58144. (B) Volcano map for all mRNAs in GSE58144. (C, D) Venn diagram analysis of DEmRNA-predicted targets and differentially expressed mRNAs in GEO.
Figure 5
Figure 5
The ceRNA network of circRNA–miRNA–mRNA in RIF. Diamonds represent circRNAs, triangles indicate miRNAs, and rounds indicate mRNAs. Node size represent the degrees of node in the ceRNA network. The node of red and green color express upregulation and downregulation, respectively.
Figure 6
Figure 6
GO and KEGG analyses of 59 mRNAs. (A) GO analysis. (B) KEGG pathway analysis.
Figure 7
Figure 7
Expression verification and structure of circRNAs. The expression of hsa_circ_0038383 (A), hsa_circ_0000115 (B) and hsa_circ_0091053 (C) in RIF compared with the controls. Structural patterns of hsa_circ_0011385 these three DEcircRNAs by circRNADb.
Figure 8
Figure 8
PPI network, hub genes, and circRNA–miRNA–mRNA subnetwork for hsa_circ_0038383. (A) PPI network of 59 DEmRNA. (B) Three hub genes extracted from the PPI network based on the MCODE algorithm. (C) The circRNA-miRNA-mRNA axes of hsa_circ_0038383.
Figure 9
Figure 9
Expression verification of miRNAs and mRNAs in the subnetwork. The expression of has-miR-196b-5p (A), has-miR-424-5p (B), HOXA9 (C), PBX1 (D) and HOXA3 (E) in endometrial tissues of RIF and the control group.
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