Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, P.R. China.
Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, Liaoning, 110001, P.R. China.
Cell Biol Int. 2018 Mar;42(3):294-302. doi: 10.1002/cbin.10894. Epub 2017 Nov 15.
Epithelial-to-mesenchymal transition (EMT) plays important roles in the migration, invasion, and metastasis of cancer cells. However, the role of Src in epidermal growth factor (EGF)-induced EMT and migration in gastric cancer cells remains to be clarified. In the current study, the effect of Src on EGF-stimulated EMT and migration was explored in gastric cancer cells. EGF induced EMT in gastric cancer cells and increased their migratory ability, which was accompanied by the phosphorylation of Src. PP2, the Src inhibitor, markedly suppressed EGF-mediated EMT and migration in gastric cancer cells. Additionally, EGF-stimulated upregulation of zinc finger E-box binding homeobox 1 (ZEB1) and zinc finger E-box binding homeobox 2 (ZEB2) was significantly repressed by PP2. Further analysis showed that EGF-stimulated phosphorylation of protein kinase B (AKT) was almost completely abolished by PP2, whereas that of extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3) was only mildly suppressed. Moreover, LY294002, the AKT inhibitor, significantly inhibited EGF-induced upregulation of ZEB1 and ZEB2 as well as EMT and migration stimulated by EGF in gastric cancer cells. However, neither ERK inhibitor nor STAT3 inhibitor repressed EGF-induced EMT-related changes. Taken together, these results suggest that Src promotes EGF-stimulated EMT and migration by upregulation of ZEB1 and ZEB2 through AKT signaling pathway in gastric cancer cells.
上皮间质转化 (EMT) 在癌细胞的迁移、侵袭和转移中发挥重要作用。然而，Src 在表皮生长因子 (EGF) 诱导的胃癌细胞 EMT 和迁移中的作用仍有待阐明。在本研究中，探讨了 Src 在 EGF 刺激的胃癌细胞 EMT 和迁移中的作用。EGF 诱导胃癌细胞发生 EMT，并增加其迁移能力，同时伴随着 Src 的磷酸化。Src 抑制剂 PP2 显著抑制 EGF 介导的胃癌细胞 EMT 和迁移。此外，PP2 显著抑制 EGF 刺激的锌指 E 盒结合同源盒 1 (ZEB1) 和锌指 E 盒结合同源盒 2 (ZEB2) 的表达上调。进一步分析表明，PP2 几乎完全抑制了 EGF 刺激的蛋白激酶 B (AKT) 的磷酸化，而对细胞外信号调节激酶 (ERK)、信号转导和转录激活因子 3 (STAT3) 的磷酸化仅轻度抑制。此外，AKT 抑制剂 LY294002 显著抑制 EGF 诱导的 ZEB1 和 ZEB2 上调以及 EGF 刺激的 EMT 和迁移。然而，ERK 抑制剂或 STAT3 抑制剂均不能抑制 EGF 诱导的 EMT 相关变化。综上所述，这些结果表明，Src 通过 AKT 信号通路促进 EGF 刺激的 EMT 和迁移，从而上调 ZEB1 和 ZEB2 在胃癌细胞中的表达。
