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MicroRNA-200 family governs ovarian inclusion cyst formation and mode of ovarian cancer spread.
Oncogene ( IF 8 ) Pub Date : 2020-03-25 , DOI: 10.1038/s41388-020-1264-x
Pui-Wah Choi 1, 2 , Wai Wing So 2 , Junzheng Yang 1 , Shubai Liu 1 , Ka Kui Tong 2 , Kin Ming Kwan 2, 3, 4 , Jamie S-L Kwok 5 , Stephen K W Tsui 5 , Shu-Kay Ng 6 , Karen H Hales 7 , Dale B Hales 7, 8 , William R Welch 9 , Christopher P Crum 9 , Wing-Ping Fong 2 , Ross S Berkowitz 1 , Shu-Wing Ng 1, 10
Affiliation  

Epidemiologic and histopathologic findings and the laying hen model support the long-standing incessant ovulation hypothesis and cortical inclusion cyst involvement in sporadic ovarian cancer development. MicroRNA-200 (miR-200) family is highly expressed in ovarian cancer. Herewith, we show that ovarian surface epithelial (OSE) cells with ectopic miR-200 expression formed stabilized cysts in three-dimensional (3D) organotypic culture with E-cadherin fragment expression and steroid hormone pathway activation, whereas ovarian cancer 3D cultures with miR-200 knockdown showed elevated TGF-β expression, mitotic spindle disorientation, increased lumenization, disruption of ROCK-mediated myosin II phosphorylation, and SRC signaling, which led to histotype-dependent loss of collective movement in tumor spread. Gene expression profiling revealed that epithelial-mesenchymal transition and hypoxia were the top enriched gene sets regulated by miR-200 in both OSE and ovarian cancer cells. The molecular changes uncovered by the in vitro studies were verified in both human and laying hen ovarian cysts and tumor specimens. As miR-200 is also essential for ovulation, our results of estrogen pathway activation in miR-200-expressing OSE cells add another intriguing link between incessant ovulation and ovarian carcinogenesis.

中文翻译:

MicroRNA-200家族控制卵巢包涵囊肿的形成和卵巢癌扩散的方式。

流行病学和组织病理学发现以及产蛋模型支持长期不间断排卵假说和皮质包涵体囊肿参与散发性卵巢癌的发展。MicroRNA-200(miR-200)家族在卵巢癌中高度表达。因此,我们显示具有异位miR-200表达的卵巢表面上皮(OSE)细胞在具有E-钙粘蛋白片段表达和类固醇激素途径激活的三维(3D)有机型培养物中形成稳定的囊肿,而具有miR-的卵巢癌3D培养物200敲低显示TGF-β表达升高,有丝分裂纺锤体定向失调,管腔增多,ROCK介导的肌球蛋白II磷酸化破坏和SRC信号转导,这导致肿瘤扩散过程中依赖于组织型的集体运动丧失。基因表达谱分析表明,上皮-间质转化和缺氧是OSE和卵巢癌细胞中受miR-200调控的最丰富的基因集。体外研究发现的分子变化已在人和产蛋鸡卵巢囊肿及肿瘤标本中得到验证。由于miR-200也是排卵必不可少的,因此我们在表达miR-200的OSE细胞中雌激素途径激活的结果在排卵不断和卵巢癌变之间增加了另一个有趣的联系。
更新日期:2020-03-25
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