Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
J Clin Invest. 2010 Feb;120(2):533-44. doi: 10.1172/JCI38379. Epub 2010 Jan 11.
Metastatic disease is responsible for the majority of human cancer deaths. Understanding the molecular mechanisms of metastasis is a major step in designing effective cancer therapeutics. Here we show that the T-box transcription factor Brachyury induces in tumor cells epithelial-mesenchymal transition (EMT), an important step in the progression of primary tumors toward metastasis. Overexpression of Brachyury in human carcinoma cells induced changes characteristic of EMT, including upregulation of mesenchymal markers, downregulation of epithelial markers, and an increase in cell migration and invasion. Brachyury overexpression also repressed E-cadherin transcription, an effect partially mediated by Slug. Conversely, inhibition of Brachyury resulted in downregulation of mesenchymal markers and loss of cell migration and invasion and diminished the ability of human tumor cells to form lung metastases in a xenograft model. Furthermore, we found Brachyury to be overexpressed in various human tumor tissues and tumor cell lines compared with normal tissues. We also determined that the percentage of human lung tumor tissues positive for Brachyury expression increased with the stage of the tumor, indicating a potential association between Brachyury and tumor progression. The selective expression of Brachyury in tumor cells and its role in EMT and cancer progression suggest that Brachyury may be an attractive target for antitumor therapies.
转移性疾病是导致大多数人类癌症死亡的主要原因。了解转移的分子机制是设计有效癌症治疗方法的重要步骤。在这里，我们表明 T 盒转录因子 Brachyury 诱导肿瘤细胞发生上皮-间充质转化 (EMT)，这是原发性肿瘤向转移进展的重要步骤。Brachyury 在人癌细胞中的过表达诱导 EMT 的特征性变化，包括间充质标志物的上调、上皮标志物的下调以及细胞迁移和侵袭的增加。Brachyury 的过表达还抑制了 E-钙粘蛋白的转录，这一效应部分是由 Slug 介导的。相反，抑制 Brachyury 导致间充质标志物的下调以及细胞迁移和侵袭的丧失，并减弱了人肿瘤细胞在异种移植模型中形成肺转移的能力。此外，我们发现与正常组织相比，Brachyury 在各种人类肿瘤组织和肿瘤细胞系中过表达。我们还确定，Brachyury 在人肺肿瘤组织中的阳性表达百分比随着肿瘤分期的增加而增加，表明 Brachyury 与肿瘤进展之间存在潜在关联。Brachyury 在肿瘤细胞中的选择性表达及其在 EMT 和癌症进展中的作用表明，Brachyury 可能是抗肿瘤治疗的一个有吸引力的靶点。
