转化生长因子-β1 通过在缺氧条件下调节血管内皮生长因子的表达参与子宫内膜异位症的发病机制。
Transforming Growth Factor-beta 1 Involved in the Pathogenesis of Endometriosis through Regulating Expression of Vascular Endothelial Growth Factor under Hypoxia.
作者信息
Yu Yue-Xin, Xiu Yin-Ling, Chen Xi, Li Ya-Li
机构信息
Department of Obstetrics and Gynecology, Chinese People's Liberation Army General Hospital and Chinese People's Liberation Army Medical School, Beijing 100853; Department of Obstetrics and Gynecology, Chinese People's Liberation Army 202 Hospital, Shenyang, Liaoning 110821, China.
Department of Obstetrics and Gynecology, Chinese People's Liberation Army 202 Hospital, Shenyang, Liaoning 110821, China.
出版信息
Chin Med J (Engl). 2017 Apr 20;130(8):950-956. doi: 10.4103/0366-6999.204112.
BACKGROUND
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.
METHODS
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.
RESULTS
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).
CONCLUSIONS
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.
背景
子宫内膜异位症（EMs）是一种常见的妇科疾病，其特征是子宫外出现类似子宫内膜的组织。缺氧诱导许多重要下游基因的表达，以调节异位子宫内膜病变的着床、存活和维持。转化生长因子-β1（TGF-β1）在子宫内膜异位症的病因中起主要作用。我们旨在确定TGF-β1在缺氧条件下是否影响子宫内膜异位症的发展和进展及其相关机制。
方法
2015年10月至2016年10月，从接受手术的有或无子宫内膜异位症的女性中获取子宫内膜组织。培养子宫内膜细胞，然后将其暴露于缺氧环境以及TGF-β1或TGF-β1抑制剂中。检测TGF-β1、血管内皮生长因子（VEGF）和缺氧诱导因子-1α（HIF-1α）的信使核糖核酸（mRNA）和蛋白质表达水平。采用双荧光素酶报告基因检测法检测TGF-β1和缺氧对VEGF启动子构建体的影响。采用学生t检验进行组间比较（单侧或双侧），P<0.05被认为具有统计学意义。
结果
子宫内膜异位症组织中TGF-β1、VEGF、HIF-1α的mRNA和蛋白质表达显著高于正常子宫内膜组织（t=2.16，P=0.042）。暴露于缺氧环境的子宫内膜异位症原代培养细胞中VEGF的mRNA和蛋白质表达增加43.8%（t=6.84，P=0.023）。TGF-β可使VEGF的mRNA水平升高12.5%，而缺氧/TGF-β1联合处理可使VEGF产生更高的产量（增加87.5%）。在存在TGF-β1（2.6倍，t=6.08，P=0.032）或缺氧（11.2倍，t=32.70，P<0.001）的情况下，VEGF启动子构建体的荧光素酶活性增加，而同时存在这两种刺激则产生显著的协同效应（18.5倍，t=33.50，P<0.001）。
结论
数据支持以下假设，即TGF-β1通过调节VEGF表达参与子宫内膜异位症的发病机制。TGF-β1和缺氧在转录水平上产生累加效应。
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