Transforming Growth Factor-beta 1 Involved in the Pathogenesis of Endometriosis through Regulating Expression of Vascular Endothelial Growth Factor under Hypoxia.
Transforming Growth Factor-beta 1 Involved in the Pathogenesis of Endometriosis through Regulating Expression of Vascular Endothelial Growth Factor under Hypoxia.
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DOI：
10.4103/0366-6999.204112
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发表时间：
2017-04-20
影响因子：
6.1
通讯作者：
Li YL
中科院分区：
文献类型：
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作者：
Yu YX;Xiu YL;Chen X;Li YL
子宫内膜异位症（EMs）是一种常见的妇科疾病，其特征是子宫外的子宫样组织。缺氧诱导许多重要的下游基因的表达，以调节异位增生性病变的植入、存活和维持。转化生长因子-β 1（Transforming growth factor-beta 1，TGF-β1）在EMs的发病机制中起重要作用。本研究旨在探讨TGF-β1在缺氧条件下是否影响EMs的发生、发展及其相关机制。从2015年10月至2016年10月接受手术的患有或不患有EM的女性中获得子宫内膜组织。培养子宫内膜细胞，然后暴露于缺氧和TGF-β1或TGF-β1抑制剂。检测TGF-β1、血管内皮生长因子（VEGF）和缺氧诱导因子-1 α（HIF-1α）的mRNA和蛋白表达水平。使用双荧光素酶报告基因测定来检查TGF-β1和缺氧对VEGF启动子构建体的影响。进行Student t检验用于组间比较（单侧或双侧），P < 0.05的值被认为具有统计学显著性。EMs组织中TGF-β1、VEGF、HIF-1α mRNA及蛋白表达均显著高于正常子宫内膜组织（t = 2.16，P = 0.042）。缺氧组EMs原代培养细胞VEGF mRNA和蛋白表达均较对照组高43.8%（t = 6.84，P = 0.023）。VEGF mRNA水平增加12.5%，而缺氧/TGF-β1联合治疗导致VEGF的产生更高（增加87.5%）。VEGF启动子构建体的荧光素酶活性在存在TGF-β1或TGF-β 2的情况下增加。（2.6倍，t = 6.08，P = 0.032）或缺氧（11.2倍，t = 32.70，P < 0.001），而同时存在两种刺激导致了显着的合作效应（18.5倍，t = 33.50，P < 0.001）。TGF-β1可能通过调节VEGF的表达而参与EMs的发病。TGF-β1和缺氧在转录水平上发生累加效应。
Endometriosis (EMs) is a common gynecological disorder characterized by endometrial-like tissue outside the uterus. Hypoxia induces the expression of many important downstream genes to regulate the implantation, survival, and maintenance of ectopic endometriotic lesions. Transforming growth factor-beta 1 (TGF-β1) plays a major role in the etiology of EMs. We aimed to determine whether TGF-β1 affects EMs development and progression and its related mechanisms in hypoxic conditions. Endometrial tissue was obtained from women with or without EMs undergoing surgery from October, 2015 to October, 2016. Endometrial cells were cultured and then exposed to hypoxia and TGF-β1 or TGF-β1 inhibitors. The messenger RNA (mRNA) and protein expression levels of TGF-β1, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor-1α (HIF-1α) were measured. A Dual-Luciferase Reporter Assay was used to examine the effect of TGF-β1 and hypoxia on a VEGF promoter construct. Student's t-test was performed for comparison among groups (one-sided or two-sided) and a value of P < 0.05 was considered statistically significant. TGF-β1, VEGF, HIF-1α mRNA, and protein expression were significantly higher in EMs tissue than that in normal endometrial tissue (t = 2.16, P = 0.042). EMs primary cultured cells exposed to hypoxia expressed 43.8% higher VEGF mRNA and protein (t = 6.84, P = 0.023). VEGF mRNA levels increased 12.5% in response to TGF-β, whereas the combined treatment of hypoxia/TGF-β1 resulted in a much higher production (87.5% increases) of VEGF. The luciferase activity of the VEGF promoter construct was increased in the presence of either TGF-β1 (2.6-fold, t = 6.08, P = 0.032) or hypoxia (11.2-fold, t = 32.70, P < 0.001), whereas the simultaneous presence of both stimuli resulted in a significant cooperative effect (18.5-fold, t = 33.50, P < 0.001). The data support the hypothesis that TGF-β1 is involved in the pathogenesis of EMs through regulating VEGF expression. An additive effect of TGF-β1 and hypoxia is taking place at the transcriptional level.