Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.
Sci Rep. 2017 Jun 15;7(1):3614. doi: 10.1038/s41598-017-03972-7.
Uterine carcinosarcomas (UCSs) are highly aggressive malignancies associated with poor prognoses and limited treatment options. These tumors are hypothesized to develop from the endometrial adenocarcinoma (EAC) through epithelial-mesenchymal transition (EMT). We test this long-standing hypothesis by depleting miR-200, a family of microRNAs critical for EMT, in EAC cell lines. Our data suggest that UCSs do not develop from EACs via EMT. Clinically more relevant, we show that miR-200 expression in UCS cells induces a robust mesenchymal-epithelial transition (MET). Using in vitro and murine xenograft models, we demonstrate decreased growth and aggressiveness of miR-200-overexpressing UCS cell lines. Whole transcriptome analysis confirmed changes consistent with an MET and also revealed changes in angiogenic genes expression. Finally, by treatment of UCS-xenografted mice with miR-200c incorporated in DOPC nanoliposomes, we demonstrate anti-tumor activities. These findings suggest that ectopic miR-200 expression using advanced microRNA therapeutics may be a potential treatment approach for patients with UCS.
子宫癌肉瘤（UCS）是一种高度侵袭性的恶性肿瘤，预后不良，治疗选择有限。这些肿瘤被认为是通过上皮-间充质转化（EMT）从子宫内膜腺癌（EAC）发展而来的。我们通过耗尽 miR-200，一种 EMT 关键的 microRNA 家族，在 EAC 细胞系中测试了这个长期存在的假说。我们的数据表明，UCS 不是通过 EMT 从 EAC 发展而来的。更具临床意义的是，我们表明 UCS 细胞中的 miR-200 表达诱导了强烈的间质-上皮转化（MET）。我们使用体外和小鼠异种移植模型，证明了 miR-200 过表达的 UCS 细胞系的生长和侵袭性降低。全转录组分析证实了与 MET 一致的变化，并且还揭示了血管生成基因表达的变化。最后，通过用 DOPC 纳米脂质体包裹的 miR-200c 处理 UCS 异种移植小鼠，我们证明了其抗肿瘤活性。这些发现表明，使用先进的 microRNA 疗法异位表达 miR-200 可能是治疗 UCS 患者的一种潜在治疗方法。
