Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
Department of Biological Chemistry, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA; Department of Medicine, School of Medicine, University of California, Irvine, Irvine, CA 92697, USA.
Dev Cell. 2014 Apr 14;29(1):59-74. doi: 10.1016/j.devcel.2014.03.006.
Epithelial cells possess remarkable plasticity, having the ability to become mesenchymal cells through alterations in adhesion and motility (epithelial-to-mesenchymal transition [EMT]). However, how epithelial plasticity is kept in check in epithelial cells during tissue development and regeneration remains to be fully understood. Here we show that restricting the EMT of mammary epithelial cells by transcription factor Ovol2 is required for proper morphogenesis and regeneration. Deletion of Ovol2 blocks mammary ductal morphogenesis, depletes stem and progenitor cell reservoirs, and leads epithelial cells to undergo EMT in vivo to become nonepithelial cell types. Ovol2 directly represses myriad EMT inducers, and its absence switches response to TGF-β from growth arrest to EMT. Furthermore, forced expression of the repressor isoform of Ovol2 is able to reprogram metastatic breast cancer cells from a mesenchymal to an epithelial state. Our findings underscore the critical importance of exquisitely regulating epithelial plasticity in development and cancer.
上皮细胞具有显著的可塑性，能够通过改变黏附和运动（上皮-间充质转化 [EMT]）成为间充质细胞。然而，在组织发育和再生过程中，上皮细胞中的上皮可塑性是如何受到控制的，仍有待充分理解。在这里，我们表明，转录因子 Ovol2 限制乳腺上皮细胞的 EMT 对于正常形态发生和再生是必需的。Ovol2 的缺失会阻断乳腺导管形态发生，耗尽干细胞和祖细胞库，并导致上皮细胞在体内发生 EMT，成为非上皮细胞类型。Ovol2 直接抑制大量 EMT 诱导物，其缺失会将 TGF-β 的反应从生长停滞转变为 EMT。此外，Ovol2 抑制型异构体的强制表达能够将转移性乳腺癌细胞从间充质状态重新编程为上皮状态。我们的研究结果强调了精细调控发育和癌症中上皮可塑性的至关重要性。
