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CircSTK40 contributes to recurrent implantation failure via modulating the HSP90/AKT/FOXO1 axis
Tianxiang Ni1,2,3,4, Qian Zhang1,2,3,4, Yan Li1,2,3,4
1Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
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.
Insights
Circular RNAs (circRNAs) like circSTK40 are implicated in recurrent implantation failure (RIF). This study reveals circSTK40 disrupts human endometrial stromal cell function, offering new therapeutic targets for RIF.
Area of Science:
- Reproductive Biology
- Epigenetics
- Molecular Biology
Background:
- Non-coding RNAs, including circular RNAs (circRNAs), are increasingly linked to recurrent implantation failure (RIF).
- The specific role of circRNAs in RIF pathogenesis is not well understood.
- This study focuses on circSTK40 as a potential factor in RIF.
Purpose of the Study:
- To investigate the role of circSTK40 in the pathogenesis of recurrent implantation failure (RIF).
- To elucidate the molecular mechanisms by which circSTK40 affects human endometrial stromal cells (ESCs).
- To explore circSTK40 as a potential therapeutic target for improving endometrial receptivity.
Main Methods:
- Microarray analysis to identify differentially expressed circRNAs.
- Functional assays including decidualization induction and TUNEL assay in ESCs.
- Biochemical assays (RNA pull-down, RIP, co-IP) to determine protein interactions.
Main Results:
- circSTK40 expression was upregulated in RIF endometrial samples.
- circSTK40 overexpression inhibited ESC decidualization but enhanced cell survival.
- circSTK40 acts as a scaffold for HSP90 and CLU, stabilizing HSP90, activating AKT, and downregulating FOXO1.
Conclusions:
- circSTK40 plays a significant role in RIF by impairing endometrial receptivity.
- The circSTK40/HSP90/AKT pathway represents a novel epigenetic mechanism in RIF pathogenesis.
- Targeting circSTK40 or related pathways may offer new therapeutic strategies for patients with RIF.
