Epithelial-mesenchymal transition (EMT) induced by TNF-α requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer.
Epithelial-mesenchymal transition (EMT) induced by TNF-α requires AKT/GSK-3β-mediated stabilization of snail in colorectal cancer.
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DOI：
10.1371/journal.pone.0056664
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Du J
中科院分区：
文献类型：
--
作者：
Wang H;Wang HS;Zhou BH;Li CL;Zhang F;Wang XF;Zhang G;Bu XZ;Cai SH;Du J
慢性炎症促进的转移被认为是癌症治疗的主要挑战。促炎细胞因子 TNFα 可诱导与上皮间质转化 (EMT) 相关的癌症侵袭和转移。然而，其根本机制尚不完全清楚。在这项研究中，我们发现TNFα诱导人HCT116细胞发生EMT，从而促进结直肠癌（CRC）的侵袭和转移。 TNFα诱导的EMT的特征是获得间充质纺锤样形态并增加N-钙粘蛋白和纤连蛋白的表达，同时减少E-钙粘蛋白和Zona occludin-1（ZO-1）的表达。 TNFα处理还增加了转录因子Snail的表达，但不增加Slug、ZEB1和Twist的表达。 Snail 的过度表达诱导 HCT116 细胞从 E-钙粘蛋白表达转变为 N-钙粘蛋白表达，这是 EMT 的一个特征。相反，Snail 的敲低显着减弱了 HCT116 细胞中 TNFα 诱导的 EMT，表明 Snail 在 TNFα 诱导的 EMT 中发挥着至关重要的作用。有趣的是，暴露于 TNFα 会迅速增加 Snail 蛋白表达和 Snail 核定位，但 mRNA 水平不会上调。最后，我们证明 TNFα 通过激活 AKT 通路并随后抑制 GSK-3β 活性并减少 Snail 与 GSK-3β 的关联来提高 Snail 的稳定性。 GSK-3β 的敲低进一步验证了我们的发现。综上所述，这些结果表明 AKT/GSK-3β 介导的 Snail 稳定是 CRC 细胞中 TNFα 诱导的 EMT 所必需的。我们的研究提供了对炎症诱导的结直肠癌转移的更好理解。
Chronic inflammation-promoted metastasis has been considered as a major challenge in cancer therapy. Pro-inflammatory cytokine TNFα can induce cancer invasion and metastasis associated with epithelial–mesenchymal transition (EMT). However, the underlying mechanisms are not entirely clear. In this study, we showed that TNFα induces EMT in human HCT116 cells and thereby promotes colorectal cancer (CRC) invasion and metastasis. TNFα-induced EMT was characterized by acquiring mesenchymal spindle-like morphology and increasing the expression of N-cadherin and fibronectin with a concomitant decrease of E-cadherin and Zona occludin-1(ZO-1). TNFα treatment also increased the expression of transcription factor Snail, but not Slug, ZEB1 and Twist. Overexpression of Snail induced a switch from E-cadherin to N-cadherin expression in HCT116 cells, which is a characteristic of EMT. Conversely, knockdown of Snail significantly attenuated TNFα-induced EMT in HCT116 cells, suggesting that Snail plays a crucial role in TNFα-induced EMT. Interestingly, exposure to TNFα rapidly increased Snail protein expression and Snail nuclear localization but not mRNA level upregulation. Finally, we demonstrated that TNFα elevated Snail stability by activating AKT pathway and subsequently repressing GSK-3β activity and decreasing the association of Snail with GSK-3β. Knockdown of GSK-3β further verified our finding. Taken together, these results revealed that AKT/GSK-3β-mediated stabilization of Snail is required for TNFα-induced EMT in CRC cells. Our study provides a better understanding of inflammation-induced CRC metastasis.
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