CircSTK40 contributes to recurrent implantation failure via modulating the HSP90/AKT/FOXO1 axis.
CircSTK40 contributes to recurrent implantation failure via modulating the HSP90/AKT/FOXO1 axis.
复制标题
CircSTK40 通过调节 HSP90/AKT/FOXO1 轴导致反复植入失败
DOI：
10.1016/j.omtn.2021.06.021
复制
发表时间：
2021-12-03
期刊：
影响因子：
--
通讯作者：
Chen ZJ
中科院分区：
文献类型：
--
作者：
Ni T;Zhang Q;Li Y;Huang C;Zhou T;Yan J;Chen ZJ
越来越多的证据表明非编码RNA与复发性着床失败（RIF）有密切关系。然而，环状RNA（circRNA）在RIF发病机制中的作用仍然很大程度上未知。微阵列分析用于鉴定差异表达的circRNA-circSTK 40。通过蜕膜化诱导和末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）实验，观察circSTK 40对人子宫内膜间质细胞（ESCs）的作用。通过RNA下拉、RNA免疫沉淀和免疫共沉淀（coIP）测定研究了circSTK 40与蛋白质之间的相互作用。我们观察到，circSTK 40表达上调RIF黄体中期子宫内膜样本。circSTK 40在ESC中的过表达抑制了蜕膜化过程，但同时增强了应激期间的细胞存活。从机制上讲，circSTK 40直接与HSP 90和CLU结合，从而作为支架阻断它们的相互作用并阻碍HSP 90的蛋白酶体降解。由此产生的高水平的HSP 90导致AKT通路的激活和FOXO 1表达的下调。AKT（MK-2206）和HSP 90（17 AAG）抑制剂均能抑制circSTK 40过表达对ESCs的影响，并以剂量依赖的方式增加ESCs的蜕膜化水平。我们的研究结果表明，RIF发病机制涉及circSTK 40活性的一种新的表观遗传机制，并为子宫内膜容受性低的患者的靶向治疗提供了基础。我们在复发性着床失败（RIF）患者的黄体中期子宫内膜中发现了一种新的上调的circRNA（circSTK 40），其通过调节HSP 90/AKT/FOXO 1轴损害RIF患者的子宫内膜容受性。我们的研究结果提示了RIF发病机制的一种新的表观遗传学机制，并为子宫内膜容受性低下患者的靶向治疗提供了基础。
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. We identified a novel upregulated circRNA (circSTK40) in midluteal-phase endometrium from recurrent implantation failure (RIF) patients, which impaired endometrial receptivity in RIF via modulating the HSP90/AKT/FOXO1 axis. Our findings indicate a novel epigenetic mechanism for RIF pathogenesis and provide a foundation for targeted treatments in patients with low endometrial receptivity.
登录
查看更多内容
影响因子：
82.9
作者：
Cha J;Sun X;Dey SK
通讯作者：
Dey SK
影响因子：
7.2
作者：
Biebl, Maximilian M.;Buchner, Johannes
通讯作者：
Buchner, Johannes
影响因子：
6.7
作者：
Franasiak, Jason M.;Holoch, Kristin J.;Yuan, Lingwen;Schammel, David P.;Young, Steven L.;Lessey, Bruce A.
通讯作者：
Lessey, Bruce A.
影响因子：
20.1
作者：
Hall, Ignacio Fernando;Climent, Montserrat;Elia, Leonardo
通讯作者：
Elia, Leonardo
影响因子：
5.6
作者：
Hoter A;El-Sabban ME;Naim HY
通讯作者：
Naim HY