文章：

在癌症发生和发展过程中定义EMT的调控网络

Regulatory networks defining EMT during cancer initiation and progression

原文发布日期：2013-01-24

DOI: 10.1038/nrc3447

类型: Review Article

开放获取: 否

要点：

1. Epithelial to mesenchymal transition (EMT) will lead to reversible reprogramming of the cell, which is defined by fundamental changes initiated and maintained by several regulatory circuits.
2. EMT is well known to be transcriptionally regulated. Several transcription factors have been described as potent enough to drive EMT. The often strong interconnection between these factors forms a solid network that drives tumour progression.
3. Recent evidence has linked EMT to epigenetic modifications. These are reversible, thus emphasizing that epigenetic modifications may contribute to EMT plasticity, which could allow cancer cells to switch back to the epithelial state on colonization at a secondary site.
4. Non-coding RNAs, and in particular microRNAs (miRNAs), are master regulators of gene expression in many biological and pathological processes. Several miRNAs are able to influence the cellular phenotype through the suppression of genes that are involved in controlling the epithelial and mesenchymal cell states. Moreover, feedback loops with transcriptional regulators of EMT further define and/or maintain a given cellular state.
5. Alternative splicing of mRNA precursors leads to the formation of different proteins from the same gene, and this directs distinct physiological functions. EMT-associated alternative splicing events are regulated by several recently identified proteins, adding a new layer to the complex regulation of EMT.
6. More recent studies have indicated that protein levels of EMT-inducing transcription factors are tightly controlled by additional mechanisms. A first level of control is found at the point of translation initiation and elongation. A complex machinery determines the stability, subcellular localization and functionality of the proteins. Misregulation of translation and post-translational regulation may contribute to EMT in cancer cells.

要点翻译：

1. 上皮间质转化（EMT）将引发细胞的可逆性重编程，这一过程由多个调控回路启动并维持的基本变化所定义。
2. 众所周知，EMT受到转录水平的调控。多种转录因子已被证实具有足够效力驱动EMT进程。这些因子间通常存在的紧密相互连接构成了推动肿瘤进展的稳固网络。
3. 最新证据显示EMT与表观遗传修饰存在关联。这些修饰具有可逆性，进一步强调表观遗传修饰可能促进EMT可塑性，使得癌细胞在转移至次级部位后能够恢复上皮状态。
4. 非编码RNA（尤其是微小RNA）是众多生物学及病理学过程中基因表达的主调控因子。多种miRNA通过抑制控制上皮细胞与间质细胞状态的基因，从而影响细胞表型。此外，与EMT转录调控因子形成的反馈回路进一步界定和/或维持特定细胞状态。
5. mRNA前体的可变剪接可使同一基因形成不同蛋白质，从而指导不同的生理功能。EMT相关可变剪接事件受若干新近发现蛋白的调控，这为EMT的复杂调控机制增添了新层次。
6. 最新研究表明，EMT诱导转录因子的蛋白质水平受到其他机制的精密调控。第一层调控见于翻译起始与延伸阶段。复杂的细胞机制决定了蛋白质的稳定性、亚细胞定位及功能性。翻译及翻译后调控的失调可能促进癌细胞发生EMT。

英文摘要：

Epithelial to mesenchymal transition (EMT) is essential for driving plasticity during development, but is an unintentional behaviour of cells during cancer progression. The EMT-associated reprogramming of cells not only suggests that fundamental changes may occur to several regulatory networks but also that an intimate interplay exists between them. Disturbance of a controlled epithelial balance is triggered by altering several layers of regulation, including the transcriptional and translational machinery, expression of non-coding RNAs, alternative splicing and protein stability.

摘要翻译： 

上皮-间充质转化（EMT）在发育过程中对驱动细胞可塑性至关重要，但在癌症进展中却是细胞的无意识行为。与EMT相关的细胞重编程不仅表明多个调控网络可能发生根本性改变，也提示这些网络之间存在密切的相互作用。受控的上皮平衡被打破，是由多层调控的改变所触发，包括转录与翻译机制、非编码RNA的表达、选择性剪接以及蛋白质稳定性。

原文链接：

Regulatory networks defining EMT during cancer initiation and progression