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miR-200a 通过 ZEB2 和 β-连环蛋白信号通路调控上皮-间充质转化至干细胞样表型。

miR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and beta-catenin signaling.

机构信息

Brain Tumour Centre and Division of Neurosurgery, Department of Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.

出版信息

J Biol Chem. 2010 Nov 19;285(47):36995-7004. doi: 10.1074/jbc.M110.133744. Epub 2010 Sep 7.

Abstract

The emerging concept of generating cancer stem cells from epithelial-mesenchymal transition has attracted great interest; however, the factors and molecular mechanisms that govern this putative tumor-initiating process remain largely elusive. We report here that miR-200a not only regulates epithelial-mesenchymal transition but also stem-like transition in nasopharyngeal carcinoma cells. We first showed that stable knockdown of miR-200a promotes the transition of epithelium-like CNE-1 cells to the mesenchymal phenotype. More importantly, it also induced several stem cell-like traits, including CD133(+) side population, sphere formation capacity, in vivo tumorigenicity in nude mice, and stem cell marker expression. Consistently, stable overexpression of miR-200a switched mesenchyme-like C666-1 cells to the epithelial state, accompanied by a significant reduction of stem-like cell features. Furthermore, in vitro differentiation of the C666-1 tumor sphere resulted in diminished stem-like cell population and miR-200a induction. To investigate the molecular mechanism, we demonstrated that miR-200a controls epithelial-mesenchymal transition by targeting ZEB2, although it regulates the stem-like transition differentially and specifically by β-catenin signaling. Our findings reveal for the first time the function of miR-200a in shifting nasopharyngeal carcinoma cell states via a reversible process coined as epithelial-mesenchymal to stem-like transition through differential and specific mechanisms.

摘要

上皮-间充质转化产生癌症干细胞的新兴概念引起了极大的兴趣;然而,控制这一假定的肿瘤起始过程的因素和分子机制在很大程度上仍未被揭示。我们在这里报告,miR-200a 不仅调节上皮-间充质转化,而且还调节鼻咽癌细胞中的干细胞样转化。我们首先表明,miR-200a 的稳定敲低促进上皮样 CNE-1 细胞向间充质表型的转化。更重要的是,它还诱导了几种干细胞样特征,包括 CD133(+)侧群、球体形成能力、裸鼠体内致瘤性和干细胞标志物表达。一致地,miR-200a 的稳定过表达将间充质样 C666-1 细胞切换到上皮状态,同时显著降低了干细胞样细胞特征。此外,C666-1 肿瘤球体的体外分化导致干细胞样细胞群体减少和 miR-200a 的诱导。为了研究分子机制,我们证明 miR-200a 通过靶向 ZEB2 来控制上皮-间充质转化,尽管它通过 β-连环蛋白信号通路以不同和特异的方式来调节干细胞样转化。我们的发现首次揭示了 miR-200a 通过上皮-间充质到干细胞样转化的可逆过程,通过不同和特异的机制在改变鼻咽癌细胞状态方面的功能。

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