CircSTK40 contributes to recurrent implantation failure via modulating the HSP90/AKT/FOXO1 axis

Abstract

Increasing evidence has revealed a close relationship between non-coding RNAs and recurrent implantation failure (RIF). However, the role of circular RNAs (circRNAs) in RIF pathogenesis remains largely unknown. Microarray analyses were used to identify the differentially expressed circRNA-circSTK40. Functional experiments, including decidualization induction and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, were performed to determine the effects of circSTK40 on human endometrial stromal cells (ESCs). The interactions between circSTK40 and proteins were investigated by RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation (coIP) assays. We observed that circSTK40 expression was upregulated in the RIF midluteal-phase endometrial samples. circSTK40 overexpression in ESCs inhibited the decidualization process but concurrently enhanced cell survival during stress. Mechanistically, circSTK40 directly bound to HSP90 and CLU, thus functioning as a scaffold to block their interactions and hinder the proteasomal degradation of HSP90. The resulting high levels of HSP90 led to the activation of the AKT pathway and downregulation of FOXO1 expression. Inhibitors of AKT (MK-2206) and HSP90 (17AAG) both abolished the effects of circSTK40 overexpression in ESCs and increased the decidualization levels in a dose-dependent manner. Our findings indicate a novel epigenetic mechanism for RIF pathogenesis involving circSTK40 activity and provide a foundation for targeted treatments in patients with low endometrial receptivity.

CircRNA-CREIT inhibits stress granule assembly and overcomes doxorubicin resistance in TNBC by destabilizing PKR

“…Circular RNA can modulate the degradation process of downstream proteins by acting as a scaffold for that protein and its E3 ligase [ 30 , 31 ]. According to the above results, we hypothesized that circRNA-CREIT might function in this way.…”

“…In recent years, the miRNA-sponge theory of circRNA has been questioned due to its low abundance and limited miRNA binding sites in most cases [ 39 ]. CircRNAs that bind with proteins have attracted much interest, usually acting as protein sponges or scaffolds of protein complexes [ 30 , 31 ]. For instance, Zhu et al reported that the cytoplasmic circRNA circZKSCSN1 could suppress the malignant behavior of hepatocellular carcinoma by competitively binding with the RBP FMRP, thereby interfering with the interaction between FMRP protein and CCAR1 mRNAs [ 40 ].…”

CircHGF suppressed cell proliferation and osteogenic differentiation of BMSCs in ONFH via inhibiting miR-25-3p binding to SMAD7

“… 35 CircRNAs are widely discovered in the eukaryotic transcriptome and function as miRNA sponges and thus to play key roles in BPs and pathogenesis. 19 , 36 , 37 Although more and more circRNAs have been identified in different species, only a minority of them have been uncovered and investigated about the biological implication. 38 In the past few years, there has been increasing interest in the roles and mechanisms of this special class of ncRNA in steroid-induced ONFH.…”

Primary Cilia Restrain PI3K-AKT Signaling to Orchestrate Human Decidualization

“…Decidualization abnormality may contribute to recurrent implantation failure [ 11 ]. In RIF endometrial samples, there is an increase of AKT activation and a decrease in FOXO1 expression [ 63 ]. Our data shows that primary cilia are important for FOXO1 activation during human decidualization.…”