Towards elucidating the connection between epithelial - mesenchymal transitions and stemness
Towards elucidating the connection between epithelial - mesenchymal transitions and stemness
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DOI：
10.1098/rsif.2014.0962
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发表时间：
2014-12-06
影响因子：
3.9
通讯作者：
Ben-Jacob, Eshel
中科院分区：
文献类型：
--
作者：
Jolly, Mohit Kumar;Huang, Bin;Ben-Jacob, Eshel
经历上皮-间质转变的上皮细胞经常被证明表现得像癌症干细胞，但精确的分子联系仍然难以捉摸。在基因水平上，干性由LIN28/let-7双抑制开关控制，而EMT/MET由miR-200/ZEB双抑制电路控制，LIN28由miR-200抑制，将两个模块耦合起来。在这里，使用专门设计的理论框架来研究 LIN28/let-7 系统的动力学，我们证明它可以作为三路开关（在低、高和中 LIN28 水平之间，称为 D、U 和混合 D/U 状态）运行，类似于 miR-200/ZEB 电路的三路操作，允许混合上皮/间质 (E/M) 表型的存在。我们发现两个电路的三种状态之间存在显着的对应关系：E-D、M-U 和 E/M-D/U。结合 LIN28 对 OCT4 的激活，我们发现混合 E/M 表型很有可能（与 E 或 M 状态相比）获得干性。结合 NF-kappa B 和 c-MYC 对 LIN28/let-7 的调节，我们发现 NF-kB 而不是 c-MYC 提高了 E/M 表型获得干性的可能性。我们的结果与新兴概念一致，即部分 EMT 可以导致干性。
Epithelial cells undergoing epithelial-to-mesenchymal transitions have often been shown to behave as cancer stem cells, but the precise molecular connection remains elusive. At the genetic level, stemness is governed by LIN28/let-7 double inhibition switch, whereas EMT/MET is controlled by miR-200/ZEB double inhibition circuit and LIN28 is inhibited by miR-200, coupling the two modules. Here, using a specially devised theoretical framework to investigate the dynamics of the LIN28/let-7 system, we show that it can operate as a three-way switch (between low, high and intermediate LIN28 levels termed the D, U and hybrid D/U states) similar to the three-way operation of the miR-200/ZEB circuit that allows for the existence of a hybrid epithelial/mesenchymal (E/M) phenotype. We find significant correspondence between the existence of the three states of the two circuits: E-D, M-U and E/M-D/U. Incorporating the activation of OCT4 by LIN28, we find that the hybrid E/M phenotype has high likelihood (when compared with either the E or M states) to gain stemness. Combining the LIN28/let-7 regulation by NF-kappa B and c-MYC, we find that NF-kB, but not c-MYC, elevates the likelihood of E/M phenotype to gain stemness. Our results are consistent with emerging concept that partial EMT can lead to stemness.