miR-23a-3p increases endometrial receptivity via CUL3 during embryo implantation

Abstract

A receptive endometrium is required in a successful embryo implantation. The ubiquitination-induced β-catenin degradation is related to the implantation failure.This study aimed to elucidate whether miR-23a-3p regulates endometrial receptivity via the modulation of β-catenin ubiquitination.The expressions of miR-23a-3p and CUL3 were detected in endometrial epithelial cells (EECs) isolated from pregnant mice and in hormone-induced EEC-like Ishikawa cells. The ubiquitination experiment was performed to explore the effect of CUL3 and miR-23a-3p on β-catenin ubiquitination level. The trophoblast attachment was detected by co-culturing JAR (choriocarcinoma cell line) spheroids with Ishikawa cell monolayers. miR-23a-3p was upregulated while CUL3 was downregulated in EECs at day 4 after pregnancy compared with day 1, as well as in hormone-induced Ishikawa cells. miR-23a-3p positively regulated the protein level of β-catenin without affecting the mRNA level. The ubiquitination and degradation of β-catenin was suppressed by miR-23a-3p while it was promoted by CUL3. Immunoprecipitation confirmed the binding between CUL3 and β-catenin. Luciferase reporter assay confirmed the target relationship between miR-23a-3p and CUL3. The ubiquitination of β-catenin was modulated by the miR-23a-3p/CUL3 pathway. The overexpression of miR-23a-3p promoted JAR spheroid attachments in Ishikawa cells.miR-23a-3p is beneficial for the endometrial receptivity and embryo implantation, whose mechanism is partly through the modulation of CUL3/β-catenin.

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

“… 45 . Furthermore, Huang et al revealed that during embryo implantation, the increased expression of miR‐23a‐3p enhances the receptivity of the endometrium by regulating the expression of CUL3 46 . Others proved that the inhibition of PAI‐1 via miR‐145 might take part in the RIF occurrence 47 .…”

Down-Regulation of circulating miR-23a-3p, miR-101-3p, and miR-let-7c in Women with Idiopathic Recurrent Pregnancy Loss

“…In human, miR-23a-3p, an intergenic miRNA, belongs to the miR-23a family and lie in the miR-23a/24/27a cluster located on the short arm of chromosome 19 (19p13.12) [31]. In a recent study conducted by Huang et al, on the expression levels of miR-23a-3p and Cullin 3 (CUL3) in mouse endometrial epithelial cells (EECs) and hormone-induced EEC-like Ishikawa cells, they found that miR-23a-3p is a key regulatory element in the endometrial receptivity and embryo implantation through the modulation of CUL3/β-catenin [32]. In 2019, Kim et al, reported that the expression pattern of miR-23a-3p is markedly altered during preimplantation embryo development [33].…”

MicroRNAs in the Regulation of Endometrial Receptivity for Embryo Implantation

“…MiRNAs identified to promote endometrial epithelial receptivity include the let-7 family [ 89 , 90 ], miR-23b [ 91 ], miR-30b/d [ 81 , 92 ], miR-183-5p [ 93 ], miR-192 [ 94 ] and miR-494 [ 81 ] ( Table 2 ). On the other hand, miR-23a-3p [ 95 ], miR-30a-3p [ 96 ], miR-30d [ 97 ], miR-125b [ 98 ], miR-145 [ 99 , 100 ], miR-200c [ 101 ], miR-429 and miR-5088 [ 102 ] are reported to hinder epithelial receptivity ( Table 2 ).…”

“…However, one study suggests that miR-23a downregulates cullin-3 (CUL3) to promote receptivity in Ishikawa cells [ 95 ], whereas other studies report that downregulation of CUL3 causes upregulation of β-catenin, ultimately impairing rather than increasing endometrial receptivity and implantation [ 89 , 91 , 93 ]. Therefore, there are conflicting results regarding the role of miR-23a in the regulation of endometrial receptivity.…”