HIF-1α介导circ-FoxO3调控子宫内膜基质细胞自噬在内异症发病中的作用机制研究

Hypoxia microenvironment plays a key role in the development of endometriosis. We found that hypoxia and HIF-1α induced autophagy of ectopic endometrial stromal cells to promote invasion and metastasis, but the regulatory mechanism involved remains unknown. Circular RNA (circRNA), a new type of non-coding RNA, is a research hotspot. Recent studies have confirmed that circ-FoxO3 is closely related to autophagy. Based on this, we found that the expression of circ-FoxO3 in the eutopic and ectopic endometrium of emdometriosis patients was reduced. ADAR1, an RNA binding protein, can regulate the expression of circ-FoxO3 by the Alu sequence on the intron of circRNA flanks. And as a target gene, ADAR1 is regulated by HIF-1α, and its expression in endometriosis patients increased. so we speculate HIF-1α may be involved in the development of endometriosis by ADAR1 regulated circ-FoxO3. We also elucidates the molecular mechanism of HIF-1α mediated ADAR1 to regulate circ-FoxO3 in the pathogenesis of autophagy in endometriosis from the tissue, cell, molecular and animal levels, which may provide theoretical basis for the pathogenesis mechanism and therapeutic targets of endometriosis.

低氧微环境在内异症发生发展中起着关键作用。课题前期研究发现低氧及其诱导因子HIF-1α可诱导异位子宫内膜基质细胞自噬促进其侵袭和转移，但具体调控机制不明。CircRNA作为一种新型非编码RNA是目前研究热点，新近研究证实circ-FoxO3与自噬发生密切相关。基于此，课题组研究发现circ-FoxO3在内异症在位和异位内膜表达降低，而ADAR1作为RNA结合蛋白可通过circRNA侧翼内含子上Alu序列调控circ-FoxO3表达，并作为靶基因受HIF-1α调控，其在内异症中表达增高。推测：HIF-1α可能通过ADAR1调控circ-FoxO3参与内异症自噬发生。为此，本项目拟从组织、细胞、分子及整体水平研究circ-FoxO3是否参与内异症自噬的发生，阐明HIF-1α介导ADAR1调控circ-FoxO3促进内异症自噬发生的分子机制，为寻找内异症源头分子机制和治疗靶点提供理论依据。

子宫内膜异位症（内异症）是妇科常见病和难治病，发病机制至今尚未明确。新近研究发现，环状RNA在疾病的发生发展中起着至关重要的作用。一种新发现的环状RNA-FoxO3 (circ-FoxO3)通过调控自噬、迁移和侵袭参与多种疾病的发生和进展，且有研究表明circ-FoxO3的表达与低氧密切相关，但其在子宫内膜异位症中的作用至今尚未有研究见报道。为此，本项目开展了一系列研究，结果证明：缺氧可以诱导自噬，而circ-FoxO3在缺氧条件下的过表达显著抑制了缺氧诱导的自噬，阻碍子宫内膜异位症细胞的迁移和侵袭。在机制上，本项目研究发现低氧促进自噬是通过HIF-1α-ADAR1-circ-FoxO3-p53轴诱导的。HIF-1α能作为转录因子与ADAR1启动子上低氧诱导元件结合，促进ADAR1表达，而高表达的ADAR1蛋白直接与circ-FoxO3 pre-mRNA结合阻断其环化，circFOXO3抑制后，p53降解减少从而诱导自噬。综上所述，本项目的研究表明circ-FoxO3是一种关键的自噬调节因子，并具有潜在的临床应用价值，可作为子宫内膜异位症的预后标志物和治疗靶点。