Tang Huifang, Massi Daniela, Hemmings Brian A, Mandalà Mario, Hu Zhengqiang, Wicki Andreas, Xue Gongda
Department of Pharmacology, Zhejiang University School of Basic Medical Sciences, Hangzhou, China.
Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
Oncotarget. 2016 Sep 20;7(38):62767-62777. doi: 10.18632/oncotarget.11232.
The transcription factor Twist is an important regulator of cranial suture during embryogenesis. Closure of the neural tube is achieved via Twist-triggered cellular transition from an epithelial to mesenchymal phenotype, a process known as epithelial-mesenchymal transition (EMT), characterized by a remarkable increase in cell motility. In the absence of Twist activity, EMT and associated phenotypic changes in cell morphology and motility can also be induced, albeit moderately, by other transcription factor families, including Snail and Zeb. Aberrant EMT triggered by Twist in human mammary tumour cells was first reported to drive metastasis to the lung in a metastatic breast cancer model. Subsequent analysis of many types of carcinoma demonstrated overexpression of these unique EMT transcription factors, which statistically correlated with worse outcome, indicating their potential as biomarkers in the clinic. However, the mechanisms underlying their activation remain unclear. Interestingly, increasing evidence indicates they are selectively activated by distinct intracellular kinases, thereby acting as downstream effectors facilitating transduction of cytoplasmic signals into nucleus and reprogramming EMT and mesenchymal-epithelial transition (MET) transcription to control cell plasticity. Understanding these relationships and emerging data indicating differential phosphorylation of Twist leads to complex and even paradoxical functionalities, will be vital to unlocking their potential in clinical settings.
转录因子Twist是胚胎发育过程中颅缝的重要调节因子。神经管的闭合是通过Twist触发的细胞从上皮表型向间充质表型的转变来实现的，这一过程称为上皮-间充质转化（EMT），其特征是细胞运动性显著增加。在缺乏Twist活性的情况下，包括Snail和Zeb在内的其他转录因子家族也能适度诱导EMT以及细胞形态和运动性的相关表型变化。首次报道，在转移性乳腺癌模型中，人类乳腺肿瘤细胞中由Twist触发的异常EMT会促使肿瘤转移至肺部。随后对多种类型癌症的分析表明，这些独特的EMT转录因子存在过表达现象，这在统计学上与更差的预后相关，表明它们在临床上具有作为生物标志物的潜力。然而，它们激活的潜在机制仍不清楚。有趣的是，越来越多的证据表明，它们被不同的细胞内激酶选择性激活，从而作为下游效应器促进细胞质信号转导至细胞核，并对EMT和间充质-上皮转化（MET）转录进行重编程，以控制细胞可塑性。了解这些关系以及表明Twist磷酸化差异会导致复杂甚至矛盾功能的新数据，对于挖掘它们在临床环境中的潜力至关重要。
