Jezkova Jana, Williams Jason S, Jones-Hutchins Ffion, Sammut Stephen J, Gollins Simon, Cree Ian, Coupland Sarah, McFarlane Ramsay J, Wakeman Jane A
North West Cancer Research Institute, College of Natural Sciences, Bangor, Gwynedd, UK.
North West Cancer Research Institute, College of Natural Sciences, Bangor, Gwynedd, UK; NISCHR Cancer Genetics Biomedical Research Unit, Welsh Government, Cathays Park, Cardiff, UK.
Oncotarget. 2014 Jun 15;5(11):3813-22. doi: 10.18632/oncotarget.1999.
The T-box transcription factor Brachyury is expressed in a number of tumour types and has been demonstrated to have cancer inducing properties. To date, it has been linked to cancer associated induction of epithelial to mesenchymal transition, tumour metastasis and expression of markers for cancer stem-like cells. Taken together, these findings indicate that Brachyury plays an important role in the progression of cancer, although the mechanism through which it functions is poorly understood. Here we show that Brachyury regulates the potential of Brachyury-positive colorectal cancer cells to proliferate and reduced levels of Brachyury result in inhibition of proliferation, with features consistent with the cells entering a quiescent-like state. This inhibition of proliferation is dependent upon p27Kip1 demonstrating that Brachyury acts to modulate cellular proliferative fate in colorectal cancer cells in a p27Kip1-dependent manner. Analysis of patient derived colorectal tumours reveals a heterogeneous localisation of Brachyury (in the nucleolus, nucleus and cytoplasm) indicating the potential complexity of the regulatory role of Brachyury in solid colorectal tumours.
T 盒转录因子 Brachyury 在多种肿瘤类型中表达，并且已被证明具有致癌特性。迄今为止，它已与癌症相关的上皮-间质转化诱导、肿瘤转移以及癌症干细胞样标志物的表达相关联。综上所述，这些发现表明 Brachyury 在癌症进展中起重要作用，尽管其发挥作用的机制尚不清楚。在这里，我们表明 Brachyury 调节 Brachyury 阳性结直肠癌细胞的增殖潜能，Brachyury 水平降低会导致增殖受到抑制，其特征与细胞进入静止样状态一致。这种增殖抑制依赖于 p27Kip1，表明 Brachyury 以 p27Kip1 依赖的方式调节结直肠癌细胞的细胞增殖命运。对患者来源的结直肠肿瘤的分析揭示了 Brachyury 的异质定位（在核仁、细胞核和细胞质中），这表明 Brachyury 在实体结直肠肿瘤中的调节作用可能具有复杂性。
