Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, 75679 Paris, France.
Sorbonne Paris Cité, Faculté de Médecine, Université Paris Descartes, Inserm Unité de Recherche U1016, Institut Cochin, CNRS (UMR 8104), 75679 Paris, France; Sorbonne Paris Cité, Université Paris Descartes, Faculté de Médecine, Hôpitaux Universitaires Paris Centre (AP-HP), Hôpital Cochin, Department of Gynecology Obstetrics II and Reproductive Medicine, 75679 Paris, France.
Free Radic Biol Med. 2017 Sep;110:1-10. doi: 10.1016/j.freeradbiomed.2017.04.362. Epub 2017 Apr 28.
The redox-sensitive nuclear factor erythroid-derived 2-like 2 (NRF2) controls endogenous antioxidant enzymes' transcription and protects against oxidative damage which is triggered by inflammation and known to favor progression of endometriosis. Glutamate Cysteine Ligase (GCL), a target gene of NRF2, is the first enzyme in the synthesis cascade of glutathione, an important endogenous antioxidant. Sixty-one patients, with thorough surgical examination of the abdominopelvic cavity, were recruited for the study: 31 with histologically-proven endometriosis and 30 disease-free women taken as controls. Expressions of NRF2 and GCL were investigated by quantitative RT-PCR and immunohistochemistry in eutopic and ectopic endometria from endometriosis-affected women and in endometrium of disease-free women. Ex vivo stromal and epithelial cells were extracted and purified from endometrial and endometriotic biopsies to explore expression of NRF2 and GCL in both stromal and epithelial compartments by western blot. Finally, in order to strengthen the role of NRF2 in endometriosis pathogenesis, we evaluated the drop of NRF2 expression in a mouse model of endometriosis using NRF2 knockout (NRF2) mice. The mRNA levels of NRF2 and GCL were significantly lower in ectopic endometria of endometriosis-affected women compared to eutopic endometria of disease-free women. The immunohistochemical analysis confirmed the decreased expression of both NRF2 and GCL in ectopic endometriotic tissues compared to eutopic endometria of endometriosis-affected and disease-free women. Immunoblotting revealed a significant decreased of NRF2 and GCL expression in epithelial and stroma cells from ectopic lesions of endometriosis-affected women compared to eutopic endometria from controls. Using a murine model of endometriosis, NRF2 implants were more fibrotic compared to wild-type with an increased weight and volume. These findings indicate that expression of the transcription factor NRF2 and its effector GCL are both profoundly deregulated in endometriotic lesions towards increased growth and fibrogenetic processes.
核因子红细胞衍生 2 样 2（NRF2）是一种对氧化损伤敏感的核转录因子，可控制内源性抗氧化酶的转录，防止由炎症引起的氧化损伤，已知这种损伤有利于子宫内膜异位症的进展。谷氨酸半胱氨酸连接酶（GCL）是 NRF2 的靶基因，是谷胱甘肽合成途径中的第一个酶，谷胱甘肽是一种重要的内源性抗氧化剂。对 61 名接受过彻底的腹盆腔手术检查的患者进行了研究：31 名患者经组织学证实患有子宫内膜异位症，30 名无疾病的女性作为对照。通过定量 RT-PCR 和免疫组织化学方法检测 NRF2 和 GCL 在子宫内膜异位症患者的在位和异位子宫内膜以及无疾病女性的子宫内膜中的表达。从子宫内膜和子宫内膜异位症活检中提取和纯化了外植体基质和上皮细胞，通过 Western blot 方法研究了 NRF2 和 GCL 在基质和上皮细胞中的表达。最后，为了加强 NRF2 在子宫内膜异位症发病机制中的作用，我们使用 NRF2 敲除（NRF2）小鼠评估了子宫内膜异位症小鼠模型中 NRF2 表达的下降。与无疾病女性的在位子宫内膜相比，子宫内膜异位症患者的异位子宫内膜中 NRF2 和 GCL 的 mRNA 水平明显降低。免疫组织化学分析证实，与子宫内膜异位症患者的在位和无疾病女性的子宫内膜相比，异位子宫内膜组织中 NRF2 和 GCL 的表达降低。免疫印迹显示，与对照组的在位子宫内膜相比，子宫内膜异位症患者异位病变的上皮细胞和基质细胞中 NRF2 和 GCL 的表达显著降低。在子宫内膜异位症的小鼠模型中，与野生型相比，NRF2 植入物的纤维化程度更高，重量和体积增加。这些发现表明，转录因子 NRF2 及其效应物 GCL 的表达在子宫内膜异位症病变中均受到严重调节，导致生长和纤维发生过程增加。
