Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
Oncogene. 2014 May 22;33(21):2737-47. doi: 10.1038/onc.2013.238. Epub 2013 Jun 10.
This study aims to investigate the significance of erythropoietin-producing hepatocellular (Eph)A2 expression and the mechanism by which EphA2 is involved in the epithelial-mensenchymal transition (EMT) of gastric cancer cells. EphA2 expression levels were upregulated and positively correlated with metastasis and EMT markers in human gastric cancer specimens. Modulation of EphA2 expression levels had distinct effects on cell proliferation, cell cycle, migration, invasion and morphology in the gastric cancer cell lines SGC7901 and AGS in vitro and in vivo. Overexpression of EphA2 resulted in the upregulation of the EMT molecular markers N-cadherin and Snail, as well as the Wnt/β-catenin targets TCF4, Cyclin-D1 and c-Myc, while silencing EphA2 using short hairpin RNA had the opposite effect. Furthermore, inhibition of the Wnt/β-catenin pathway by XAV939 negated the effect of EphA2 overexpression, whereas activation of the Wnt/β-catenin pathway by LiCl impaired the effect of the EphA2 knockdown on EMT. These observations demonstrate that EphA2 upregulation is a common event in gastric cancer specimens that is closely correlated with cancer metastasis and that EphA2 promotes EMT of gastric cancer cells through activation of Wnt/β-catenin signaling.
本研究旨在探讨红细胞生成素产生肝细胞 (Eph)A2 表达的意义以及 EphA2 如何参与胃癌细胞的上皮-间充质转化 (EMT)。 EphA2 表达水平上调，并与人胃癌标本中的转移和 EMT 标志物呈正相关。 EphA2 表达水平的调节对体外和体内胃癌细胞系 SGC7901 和 AGS 的细胞增殖、细胞周期、迁移、侵袭和形态有明显影响。 EphA2 的过表达导致 EMT 分子标志物 N-钙黏蛋白和 Snail 的上调，以及 Wnt/β-连环蛋白靶基因 TCF4、Cyclin-D1 和 c-Myc 的上调，而使用短发夹 RNA 沉默 EphA2 则产生相反的效果。此外，用 XAV939 抑制 Wnt/β-连环蛋白通路消除了 EphA2 过表达的作用，而用 LiCl 激活 Wnt/β-连环蛋白通路则削弱了 EphA2 敲低对 EMT 的作用。这些观察结果表明，EphA2 上调是胃癌标本中的常见事件，与癌症转移密切相关，EphA2 通过激活 Wnt/β-连环蛋白信号促进胃癌细胞的 EMT。
