Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, 110042, PR China.
Department of Gynecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, 110042, PR China.
Mol Cell Endocrinol. 2019 Aug 20;494:110486. doi: 10.1016/j.mce.2019.110486. Epub 2019 Jun 21.
Endometriosis (EMs) is an estrogen-dependent multifactorial disease. Inhibition of estrogen in endometrial cells contributes to their failure to form lesions in ectopic sites. However, whether reducing or suppressing the inhibitory effect of estrogen results in the establishment of ectopic lesions remains unclear. The BCAR3 gene induces estrogen resistance in estrogen-dependent breast cancer cells and promotes cell migration, invasion, and epithelial-mesenchymal transition (EMT). However, the expression of BCAR3 in endometriosis and its effect on endometrial cell function and the anti-estrogen effect of endometriosis have not been reported. These issues are addressed in the present study.
The study included 32 cases of ectopic endometrium and eutopic endometrium in patients with endometriosis and 31 cases of normal endometrium as controls. The expression of BCAR3 and microRNA (miR)-126-5p was detected by real-time PCR, immunohistochemistry, and western blotting. The effects of BCAR3 and miR-126-5p on the morphology and biological behavior of eutopic endometrial cells were verified using lentivirus overexpression and a vector knockdown model, the CCK-8 assay, Transwell experiments, and estrogen intervention experiments using primary cultures of epithelial and stromal cells.
The BCAR3 gene was highly expressed in ectopic endometrium and the eutopic endometrium of patients with endometriosis, and the expression level was higher in stage III-IV patients than in stage I-II patients. In vitro cell experiments showed that miR-126-5p negatively regulated the expression of BCAR3 and its effect on the migration and invasion of stromal cells. Low expression of miR-126-5p and high expression of BCAR3 promoted endometriosis stromal cell migration and invasion. Assessment of EMT in endometriosis compared with eutopic endometrium showed that the expression of vimentin was significantly increased and the expression of E-cadherin was significantly decreased in ectopic endometrium. Estrogen promoted EMT in eutopic endometrial epithelial cells and this effect was reversed by estrogen inhibitors. BCAR3 had no direct effect on EMT and did not act synergistically with estrogen on promoting EMT.
miR-126-5p negatively regulated BCAR3 expression in eutopic endometriosis, enhanced the migration and invasion of endometrial cells, and promoted the occurrence of endometriosis. BCAR3 did not induce EMT and had no synergistic effect with estrogen, but its inhibition of anti-estrogen function may provide new insight into the mechanism of local estrogen action in endometriosis.
子宫内膜异位症（EMs）是一种雌激素依赖性的多因素疾病。在子宫内膜细胞中抑制雌激素有助于防止异位部位形成病变。然而，减少或抑制雌激素的抑制作用是否会导致异位病变的建立尚不清楚。BCAR3 基因在雌激素依赖性乳腺癌细胞中诱导雌激素抵抗，并促进细胞迁移、侵袭和上皮-间充质转化（EMT）。然而，BCAR3 在子宫内膜异位症中的表达及其对子宫内膜细胞功能的影响，以及子宫内膜异位症中雌激素的抗雌激素作用尚未有报道。本研究旨在探讨这些问题。
本研究纳入了 32 例子宫内膜异位症患者的异位内膜和在位内膜，以及 31 例正常内膜作为对照。采用实时 PCR、免疫组化和 Western blot 检测 BCAR3 和 microRNA（miR）-126-5p 的表达。利用慢病毒过表达和载体敲低模型、CCK-8 检测、Transwell 实验以及原代上皮和间质细胞的雌激素干预实验，验证 BCAR3 和 miR-126-5p 对在位子宫内膜细胞形态和生物学行为的影响。
BCAR3 基因在异位内膜和子宫内膜异位症患者的在位内膜中高表达，且在 III-IV 期患者中的表达水平高于 I-II 期患者。体外细胞实验表明，miR-126-5p 负调控 BCAR3 的表达，并对基质细胞的迁移和侵袭产生影响。miR-126-5p 低表达和 BCAR3 高表达促进子宫内膜异位症基质细胞的迁移和侵袭。与在位内膜相比，子宫内膜异位症中 EMT 的评估显示，异位内膜中波形蛋白的表达显著增加，E-钙黏蛋白的表达显著降低。雌激素促进了在位子宫内膜上皮细胞的 EMT，雌激素抑制剂可逆转这一作用。BCAR3 对 EMT 没有直接作用，也没有与雌激素协同促进 EMT。
miR-126-5p 负调控在位子宫内膜异位症中 BCAR3 的表达，增强子宫内膜细胞的迁移和侵袭，促进子宫内膜异位症的发生。BCAR3 不会诱导 EMT，也不会与雌激素产生协同作用，但它抑制抗雌激素功能可能为子宫内膜异位症中局部雌激素作用的机制提供新的见解。
