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Vav proteins maintain epithelial traits in breast cancer cells using miR-200c-dependent and independent mechanisms.
Oncogene ( IF 8 ) Pub Date : 2019-Jan-01 , DOI: 10.1038/s41388-018-0433-7
L Francisco Lorenzo-Martín 1, 2, 3 , Carmen Citterio 1, 2 , Mauricio Menacho-Márquez 1, 2, 3, 4 , Javier Conde 1, 2 , Romain M Larive 1, 2, 5 , Sonia Rodríguez-Fdez 1, 2 , Ramón García-Escudero 3, 6 , Javier Robles-Valero 1, 2, 3 , Myriam Cuadrado 1, 2, 3 , Isabel Fernández-Pisonero 1, 2, 3 , Mercedes Dosil 1, 2, 3, 7 , María A Sevilla 3, 8 , María J Montero 3, 8 , Pedro M Fernández-Salguero 9 , Jesús M Paramio 3, 6 , Xosé R Bustelo 1, 2, 3
Affiliation  

The bidirectional regulation of epithelial-mesenchymal transitions (EMT) is key in tumorigenesis. Rho GTPases regulate this process via canonical pathways that impinge on the stability of cell-to-cell contacts, cytoskeletal dynamics, and cell invasiveness. Here, we report that the Rho GTPase activators Vav2 and Vav3 utilize a new Rac1-dependent and miR-200c-dependent mechanism that maintains the epithelial state by limiting the abundance of the Zeb2 transcriptional repressor in breast cancer cells. In parallel, Vav proteins engage a mir-200c-independent expression prometastatic program that maintains epithelial cell traits only under 3D culture conditions. Consistent with this, the depletion of endogenous Vav proteins triggers mesenchymal features in epithelioid breast cancer cells. Conversely, the ectopic expression of an active version of Vav2 promotes mesenchymal-epithelial transitions using E-cadherin-dependent and independent mechanisms depending on the mesenchymal breast cancer cell line used. In silico analyses suggest that the negative Vav anti-EMT pathway is operative in luminal breast tumors. Gene signatures from the Vav-associated proepithelial and prometastatic programs have prognostic value in breast cancer patients.

中文翻译:

Vav 蛋白使用 miR-200c 依赖性和独立机制维持乳腺癌细胞的上皮特征。

上皮间质转化 (EMT) 的双向调节是肿瘤发生的关键。Rho GTP酶通过影响细胞间接触稳定性、细胞骨架动力学和细胞侵袭性的规范途径调节这一过程。在这里,我们报告 Rho GTPase 激活剂 Vav2 和 Vav3 利用新的 Rac1 依赖性和 miR-200c 依赖性机制,通过限制 Zeb2 转录抑制因子在乳腺癌细胞中的丰度来维持上皮状态。与此同时,Vav 蛋白参与了一个独立于 mir-200c 的表达前转移程序,该程序仅在 3D 培养条件下维持上皮细胞特征。与此一致,内源性 Vav 蛋白的消耗会触发上皮样乳腺癌细胞的间充质特征。反过来,根据所使用的间充质乳腺癌细胞系,Vav2 活性版本的异位表达使用 E-钙粘蛋白依赖性和独立机制促进间充质-上皮转化。计算机分析表明负 Vav 抗 EMT 途径在管腔乳腺肿瘤中有效。来自 Vav 相关的前上皮和前转移程序的基因特征在乳腺癌患者中具有预后价值。
更新日期:2018-08-07
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