子宫内膜异位症中乙酰辅酶A羧化酶1调控异常增殖和侵袭的机制研究

Endometriosis is an estrogen-dependent inflammatory disease. Although it is a benign disease, it has malignant biological characteristics, such as active proliferation and invasion. At present, the pathogenesis of endometriosis is unclear and therapy methods is still limited. A growing evidence shows strong association between Acetyl-CoA carboxylase 1 (ACC1) and the proliferation and invasion of tumor cells, but the regulation mechanism of ACC1 in endometriosis in not clear yet. Our previously published work demonstrated the abundant PGE2 in the abdominal cavity of patients with endometriosis promotes the growth of ectopic lesions by regulating estrogen metabolism, but the specific mechanism is still unknown. The preliminary experimental data showed that expression of ACC1 were much lower in human ectopic endometrial stromal cells (ESCs) than eutopic endometrial stromal cells (EMs) from the same person. PGE2 stimulated ACC1 expression through MAPK signaling pathway in ESCs. After administration of ACC1 inhibitor TOFA, the promotion effect of PGE2 on proliferation and invasion of endometriotic stromal cells were further up-regulated, suggesting that ACC1 mediates the regulation of PGE2 on endometriosis. To solve these problems, first, by knockdown and overexpression of ACC1, we will verify the possible regulation of PGE2 induced cellular function by ACC1. Secondly, we will further use coimmunoprecipitation assay and chromatin immunoprecipitation to investigate the binding capacity between downstream transcription factors and ACC1. Meanwhile, we will construct xenograft nude mice model of endometriosis and use adenovirus transfection to overexpress ACC1, in order to determine the role of ACC1 on the proliferation and invasion of endometriosis lesions. In conclusion, the aim of the study is to reveal the possible relationship among ACC1, PGE2, MAPK and the proliferation and invasion of endometriosis, and further identifying new molecular targets for the treatment of endometriosis.

内异症是雌激素依赖的炎性疾病，良性病但具有增殖和侵袭活跃的恶性行为。目前发病机制不清，治疗手段有限。ACC1是调控肿瘤增殖侵袭的重要环节，但对内异症病灶异常增殖和侵袭的作用尚不明确。我们既往研究发现，内异症患者腹腔高表达的炎性因子PGE2通过调控雌激素的合成促进异位病灶的生长，但具体机制不清。我们前期数据显示，ACC1在内异症的异位内膜低表达，PGE2通过MAPK通路抑制ACC1的表达；ACC1被抑制后，PGE2对细胞增殖和侵袭相关因子的表达增强，提示ACC1介导PGE2对内异症的调控。因此，我们拟通过敲低和过表达ACC1，验证ACC1对PGE2及细胞增殖和侵袭的作用；采用免疫共沉淀和染色质免疫沉淀，探讨MAPK下游转录因子与ACC1的结合力；构建异种移植的裸鼠内异症模型，明确ACC1对异位病灶增殖和侵袭的影响。旨在揭示ACC1-PGE2-MAPK-细胞增殖侵袭的具体机制，寻找治疗新靶点。

子宫内膜异位症（内异症）是雌激素依赖的炎性疾病，良性病但具有增殖和侵袭活跃的恶性行为。目前内异症发病机制不清，治疗手段有限。乙酰辅酶A羧化酶1（Acetyl-CoA carboxylase 1, ACC1）是调控肿瘤增殖侵袭的重要环节，但对内异症病灶异常增殖和侵袭的作用尚不明确。我们对内异症中异常低表达的ACC1是否接受异位病灶高表达的炎性因子前列腺素E2（prostaglandin E2, PGE2）的调控以及对异位病灶增殖和侵袭的影响进行了深入的研究；同时对铁死亡诱导剂FIN56是否能够通过促进ACC1及下游烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶4（nicotinamide adenine dinucleotide phosphate oxidases, NOX4）的表达从而发挥对内异症的治疗作用及相关机制进行了初步探究；最后，对卵巢型内异症是否影响内异症合并不孕患者妊娠结局进行了探讨。首先，本研究证明了内异症异位内膜间质细胞中过表达的PGE2磷酸化激活丝裂原活化蛋白激酶(mitogen-activated protein kinases, MAPKs) 信号通路，下游活化的转录因子蛋白c-Jun与CREB形成转录复合体，抑制CREB与ACC1 DNA启动子区的结合，抑制ACC1的转录和表达。而低表达ACC1促进了内异症细胞的增殖和侵袭，表明ACC1是调控内异症病灶发生发展的关键因子。其次，证明了铁死亡诱导剂FIN56能够通过上调ACC1的表达及功能，从而激活MAPK信号通路，调控铁死亡关键因子NOX4的表达，促进脂质过氧化，进而抑制内异症异位间质细胞的生长，为FIN56及ACC1成为内异症的治疗的可能药物及分子靶点提供初步理论依据。最后，我们揭示了巧囊大小、单双侧、既往手术史对卵巢型内异症不孕患者卵巢储备、卵巢刺激反应性及妊娠结局的影响，为内异症不孕患者助孕时机和策略的选择提供临床指导，文章发表于 Ovarian Res. 2022 Oct 22;15(1):116。