Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β1/Snail Activation Aggravates Invasive Growth of Cholangiocarcinoma
Epithelial-Mesenchymal Transition Induced by Transforming Growth Factor-β1/Snail Activation Aggravates Invasive Growth of Cholangiocarcinoma
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DOI：
10.2353/ajpath.2010.090747
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发表时间：
2010-07-01
影响因子：
6
通讯作者：
Nakanuma, Yasuni
中科院分区：
文献类型：
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作者：
Sato, Yasunori;Harada, Kenichi;Nakanuma, Yasuni
上皮间质转化是癌症侵袭和转移启动的重要机制。本研究旨在阐明上皮-间质转化在胆管癌进展中的参与。用转化生长因子-β 1 (TGF-β 1) 处理胆管癌细胞系 CCKS-1 和 TFK-1，并检查表型变化和侵袭活性。使用胆管癌的组织切片进行免疫组织化学分析。在体外，TGF-β 1 诱导 CCKS-1 和 TFK-1 的间充质特征，其特征是 E-钙粘蛋白和细胞角蛋白 19 表达减少以及间充质标志物（如波形蛋白和 S100A4）的诱导。 TGF-β1还诱导Snail的核表达，两种细胞系的侵袭活性均显着增加。使用小鼠异种移植模型的研究表明，TGE-β1 加剧了 CCKS-1 的腹膜传播。同时施用可溶性 TGF-β II 型受体可抑制 TGF-β 1 引起的所有这些变化。在体内，37 例胆管癌病例中的 6 例（16%）在其细胞核中显示出明显的 Snail 免疫反应性。在这6例中，细胞角蛋白19的免疫表达显着降低，波形蛋白的表达显着增加。 Snail表达与淋巴结转移和患者较差的生存率显着相关。这些结果表明TGF-β1/Snail激活诱导的上皮-间质转化与不良预后密切相关。 （Am J Pathol 2010，177：141-152；DOI：10.2353/ajpath.2010.090747）
Epithelial-mesenchymal transition is an important mechanism behind initiation of cancer invasion and metastasis. This study was performed to clarify the involvement of epithelial-mesenchymal transition in the progression of cholangiocarcinoma. Cholangiocarcinoma cell lines, CCKS-1 and TFK-1, were treated with transforming growth factor-beta 1 (TGF-beta 1), and the phenotypic changes and invasive activity were examined. Immunohistochemical analysis was performed using tissue sections of cholangiocarcinoma. In vitro, TGF-beta 1 induced mesenchymal features in CCKS-1 and TFK-1 characterized by the reduction of E-cadherin and cytokeratin 19 expression and the induction of mesenchymal markers, such as vimentin and S100A4. TGF-beta 1 also induced the nuclear expression of Snail, and the invasive activity was significantly increased in both cell lines. Studies using a mouse xenograft model showed that TGE-beta 1 worsened the peritoneal dissemination of CCKS-1. All these changes by TGF-beta 1 were inhibited by the simultaneous administration of soluble TGF-beta type II receptor. In vivo, six (16%) of 37 cholangiocarcinoma cases showed marked immunoreactivity of Snail in their nuclei. In these six cases, the immuno-expression of cytokeratin 19 was significantly reduced, and the expression of vimentin was significantly increased. The Snail expression significantly correlated with the lymph node metastasis and a poor survival rate of the patients. These results suggest that epithelial-mesenchymal transition induced by TGF-beta 1/Snail activation is closely associated with in a poor prognosis. (Am J Pathol 2010, 177:141-152; DOI: 10.2353/ajpath.2010.090747)