A novel role of the Sp/KLF transcription factor KLF11 in arresting progression of endometriosis.
A novel role of the Sp/KLF transcription factor KLF11 in arresting progression of endometriosis.
复制标题
DOI：
10.1371/journal.pone.0060165
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Urrutia R
中科院分区：
文献类型：
--
作者：
Daftary GS;Zheng Y;Tabbaa ZM;Schoolmeester JK;Gada RP;Grzenda AL;Mathison AJ;Keeney GL;Lomberk GA;Urrutia R
子宫内膜异位症影响约10%的年轻育龄妇女。疾病相关的盆腔疼痛、不孕症和性功能障碍具有显著的不良临床、社会和经济影响。由于确切的病因仍然难以捉摸，目前的治疗策略是经验性的，没有重点，往往不能令人满意。缺乏合适的遗传模型阻碍了该领域的进一步转化研究。在这项研究中，我们评估了Sp/KLF转录因子KLF 11/Klf 11在子宫内膜异位症发病机制中的作用。KLF 11是一种人类疾病相关基因，在病因学上与糖尿病、子宫肌瘤和癌症有关。我们发现KLF 11的表达在人类子宫内膜异位症植入物中减少，并进一步研究了其在Klf 11-/-敲除小鼠手术诱导的子宫内膜异位症病变中的致病作用。与野生型对照相比，Klf 11-/-动物中的病变较大，并与类似晚期人类疾病的多产纤维化粘连相关。为了确定表型特异性，还在Klf 9-/-动物中产生子宫内膜异位症。与Klf 11-/-小鼠不同，Klf 9-/-动物的病变既不大，也不与显著的纤维化反应相关。KLF 11还与子宫内膜间质细胞中胶原、MMP和TGF-β家族的关键纤维化相关基因启动子区的特异性元件结合。KLF 11结合导致这些基因的转录抑制。总之，我们确定了KLF 11在预防子宫内膜异位症新发疾病相关纤维化中的新的致病作用。我们的模型在体内验证了Klf 11信号失调的表型后果。此外，它提供了一个强大的手段，不仅为进一步详细的机制研究，而且有能力测试任何新兴的翻译衍生物，从而扩大子宫内膜异位症的治疗范围和能力。
Endometriosis affects approximately 10% of young, reproductive-aged women. Disease associated pelvic pain; infertility and sexual dysfunction have a significant adverse clinical, social and financial impact. As precise disease etiology has remained elusive, current therapeutic strategies are empiric, unfocused and often unsatisfactory. Lack of a suitable genetic model has impaired further translational research in the field. In this study, we evaluated the role of the Sp/KLF transcription factor KLF11/Klf11 in the pathogenesis of endometriosis. KLF11, a human disease-associated gene is etiologically implicated in diabetes, uterine fibroids and cancer. We found that KLF11 expression was diminished in human endometriosis implants and further investigated its pathogenic role in Klf11-/- knockout mice with surgically induced endometriotic lesions. Lesions in Klf11-/- animals were large and associated with prolific fibrotic adhesions resembling advanced human disease in contrast to wildtype controls. To determine phenotype-specificity, endometriosis was also generated in Klf9-/- animals. Unlike in Klf11-/- mice, lesions in Klf9-/- animals were neither large, nor associated with a significant fibrotic response. KLF11 also bound to specific elements located in the promoter regions of key fibrosis-related genes from the Collagen, MMP and TGF-β families in endometrial stromal cells. KLF11 binding resulted in transcriptional repression of these genes. In summary, we identify a novel pathogenic role for KLF11 in preventing de novo disease-associated fibrosis in endometriosis. Our model validates in vivo the phenotypic consequences of dysregulated Klf11 signaling. Additionally, it provides a robust means not only for further detailed mechanistic investigation but also the ability to test any emergent translational ramifications thereof, so as to expand the scope and capability for treatment of endometriosis.
登录
查看更多内容
影响因子：
4.8
作者：
Cook, T;Gebelein, B;Urrutia, R
通讯作者：
Urrutia, R
DOI：
10.1016/s0889-8545(05)70302-8
发表时间：
1997-06-01
影响因子：
3.2
作者：
Eskenazi, B;Warner, ML
通讯作者：
Warner, ML
影响因子：
1.5
作者：
Hoeger, KM;Guzick, DS
通讯作者：
Guzick, DS
影响因子：
4.8
作者：
Buttar, Navtej S.;DeMars, Cathrine J.;Urrutia, Raul
通讯作者：
Urrutia, Raul
影响因子：
--
作者：
Daftary, Gaurang S.;Tetrault, Amy M.;Taylor, Hugh S.
通讯作者：
Taylor, Hugh S.