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首页> 外文期刊>Endocrinology >Krüppel-Like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis
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Krüppel-Like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis

机译：在子宫内膜异位症小鼠模型中，子宫内膜细胞中的Krüppel-Like因子9缺乏促进异位病灶的形成与激活的缺口和刺猬信号有关

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Endometriosis, a steroid hormone-dependent disease characterized by aberrant activation of estrogen receptor signaling and progesterone resistance, remains intractable because of the complexity of the pathways underlying its manifestation. We previously showed that eutopic endometria of women with endometriosis exhibit lower expression of Krüppel-like factor 9 (KLF9), a progesterone receptor coregulator in the uterus, relative to that of women without disease. Here we examined whether loss of endometrial KLF9 expression causes ectopic lesion establishment using syngeneic wild-type (WT) mice as recipients of endometrial fragments from WT and Klf9 null donors. We found significantly higher incidence of ectopic lesions with Klf9 null than WT endometria 8 weeks after tissue injection into the intraperitoneal cavity. The increased incidence of lesion establishment with Klf9 null endometria was associated with a higher expression ratio of estrogen receptor 2 isoform relative to that of estrogen receptor 1 and attenuated progesterone receptor levels in endometriotic stromal cells. PCR array analyses of Notch and Hedgehog signaling components in ectopic lesions demonstrated up-regulated expression of select genes (Jag 2, Shh, Gli1, and Stil 1) in Klf9 null lesions relative to that in WT lesions. Immunohistochemical analyses showed increased levels of Notch intracellular domain and Sonic Hedgehog proteins in Klf9 null lesions relative to that in WT lesions, confirming pathway activation. WT recipients with Klf9 null lesions displayed lower systemic levels of TNFα and IL-6 and higher soluble TNF receptor 1 than corresponding recipients with WT lesions. Our results suggest that endometrial KLF9 deficiency promotes endometriotic lesion establishment by the coincident deregulation of Notch-, Hedge-hog-, and steroid receptor-regulated pathways.
机译：子宫内膜异位症是一种以类固醇激素依赖性疾病为特征的疾病，其特征在于雌激素受体信号转导异常激活和孕酮抵抗，但由于其表现途径的复杂性，仍然难以治疗。我们以前表明，子宫内膜异位症妇女的异位子宫内膜相对于没有疾病的妇女，其子宫内孕激素受体调节剂Krüppel样因子9（KLF9）的表达较低。在这里，我们检查了子宫内膜KLF9表达的缺失是否导致使用同基因野生型（WT）小鼠作为来自WT和Klf9空供体的子宫内膜片段的受体的异位病变的建立。我们发现，将组织注射入腹腔后8周，Klf9无效的异位病变的发生率比WT子宫内膜高。与子宫内膜异位基质细胞相比，相对于雌激素受体1，雌激素受体2同工型的更高的表达率与Klf9无效子宫内膜异位症的发病率增加有关。异位病变中Notch和Hedgehog信号组件的PCR阵列分析表明，相对于WT病变，Klf9 null病变中选择基因（Jag 2，Shh，Gli1和Stil 1）的表达上调。免疫组织化学分析显示，相对于WT病变，Klf9无效病变中Notch细胞内结构域和Sonic Hedgehog蛋白水平升高，证实了途径激活。带有Klf9无效病变的WT接受者比相应的WT病变的接受者表现出更低的全身TNFα和IL-6水平和更高的可溶性TNF受体1。我们的结果表明，子宫内膜KLF9缺乏症通过同时解除Notch-，Hedge-hog-和类固醇受体调节的通路来促进子宫内膜异位病变的建立。

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