FoxA2 通过转录抑制 IGF2BP1 抑制子宫内膜异位症中 ERβ 介导的细胞焦亡。
FoxA2 represses ERβ-mediated pyroptosis in endometriosis by transcriptionally inhibiting IGF2BP1.
机构信息
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, PR China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, PR China.
出版信息
Exp Cell Res. 2023 May 1;426(1):113539. doi: 10.1016/j.yexcr.2023.113539. Epub 2023 Mar 6.
BACKGROUND
Endometriosis is a severe disease which is associated with excessive activation of pyroptosis. Our present research aimed to investigate the function of Forkhead Box A2 (FoxA2) in regulating pyroptosis in endometriosis.
METHODS
IL-1β and IL-18 concentrations were assessed using ELISA. Cell pyroptosis was analyzed using flow cytometry. TUNEL staining was performed to determine human endometrial stromal cells (HESC) death. Moreover, ERβ mRNA stability was assessed using RNA degradation assay. Finally, the binding relationships between FoxA2, IGF2BP1 and ERβ were verified by dual-luciferase reporter system, ChIP, RIP and RNA pull-down assays.
RESULTS
Our results revealed that IGF2BP1 and ERβ were significantly upregulated in ectopic endometrium (EC) tissues of endometriosis patients compared to that in eutopic endometrium (EU) tissues as well as IL-18 and IL-1β levels. Loss-of-function experiments subsequently demonstrated that either IGF2BP1 knockdown or ERβ knockdown could repress HESC pyroptosis. In addition, IGF2BP1 upregulation promoted the pyroptosis in endometriosis by binding to ERβ and promoting ERβ mRNA stability. Our further research displayed that FoxA2 upregulation suppressed HESC pyroptosis by interacting with IGF2BP1 promoter.
CONCLUSION
Our research proved that FoxA2 upregulation downregulated ERβ by transcriptionally inhibiting IGF2BP1, thereby repressing pyroptosis in endometriosis.
背景
子宫内膜异位症是一种严重的疾病，与细胞焦亡的过度激活有关。本研究旨在探讨叉头框蛋白 A2（FoxA2）在调控子宫内膜异位症中细胞焦亡中的作用。
方法
采用 ELISA 法检测白细胞介素-1β（IL-1β）和白细胞介素-18（IL-18）的浓度。采用流式细胞术分析细胞焦亡。采用 TUNEL 染色法检测人子宫内膜基质细胞（HESC）的死亡。此外，采用 RNA 降解试验评估 ERβ mRNA 的稳定性。最后，通过双荧光素酶报告系统、染色质免疫沉淀（ChIP）、RNA 免疫沉淀（RIP）和 RNA 下拉实验验证 FoxA2、IGF2BP1 和 ERβ 之间的结合关系。
结果
与正常子宫内膜（EU）组织相比，子宫内膜异位症患者的异位内膜（EC）组织中 IGF2BP1 和 ERβ 明显上调，IL-18 和 IL-1β 水平也升高。功能丧失实验进一步表明，IGF2BP1 敲低或 ERβ 敲低均可抑制 HESC 焦亡。此外，IGF2BP1 上调通过与 ERβ 结合并促进 ERβ mRNA 稳定性促进子宫内膜异位症中的焦亡。我们的进一步研究表明，FoxA2 上调通过与 IGF2BP1 启动子相互作用抑制 ERβ 转录，从而抑制子宫内膜异位症中的细胞焦亡。
结论
本研究证明 FoxA2 上调通过转录抑制 IGF2BP1 下调 ERβ，从而抑制子宫内膜异位症中的细胞焦亡。
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