TNF-α Induces Epithelial-Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism
TNF-α Induces Epithelial-Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism
复制标题
DOI：
10.1158/1541-7786.mcr-12-0160
复制
发表时间：
2012-08-01
影响因子：
5.2
通讯作者：
Sun, Kuang-Hui
中科院分区：
文献类型：
--
作者：
Ho, Ming-Yi;Tang, Shye-Jye;Sun, Kuang-Hui
肿瘤坏死因子 -α（TNF -α）是一种具有抗肿瘤特性的细胞因子。然而，肿瘤细胞或基质细胞低剂量、长期产生TNF -α可能会促进肿瘤生长和转移。肾细胞癌（RCC）患者的血清TNF -α水平显著升高。在此，我们发现TNF -α通过抑制E -钙黏蛋白、上调波形蛋白、激活基质金属蛋白酶9（MMP9）以及侵袭活性，诱导上皮 - 间质转化（EMT）并促进肾细胞癌的致瘤性。此外，在肾细胞癌细胞中，TNF -α处理通过磷脂酰肌醇3 -激酶/蛋白激酶B（PI3K/Akt）通路介导的丝氨酸 - 9磷酸化抑制糖原合成酶激酶3β（GSK - 3β）的活性。LY294002对PI3K/Akt的抑制重新激活了GSK - 3β，并抑制了TNF -α诱导的肾细胞癌细胞的上皮 - 间质转化。氯化锂（LiCl）使GSK - 3β失活显著增加了肾细胞癌细胞的MMP9活性和上皮 - 间质转化。将组成型激活的GSK - 3β转导到肾细胞癌细胞中激活GSK - 3β，抑制了TNF -α介导的软琼脂中不依赖贴壁的生长以及在裸鼠中的致瘤性。相反，过表达一种激酶缺陷型的GSK - 3β增强了上皮 - 间质转化、不依赖贴壁的生长，并极大地提高了体内的致瘤性。最重要的是，在人肾细胞癌肿瘤组织中观察到GSK - 3β活性降低15倍，E -钙黏蛋白减少3倍，波形蛋白增加2倍。这些结果表明，GSK - 3β失活在TNF -α介导的肾细胞癌肿瘤发生中起关键作用。《分子癌症研究》；10(8)；1109 - 19。（C）2012美国癌症研究协会。
TNF-alpha is a cytokine with antitumorigenic property. In contrast, low dose, chronic TNF-alpha production by tumor cells or stromal cells may promote tumor growth and metastasis. Serum levels of TNF-alpha are significantly elevated in renal cell carcinoma (RCC) patients. Here, we showed that TNF-alpha induced epithelial-mesenchymal transition (EMT) and promoted tumorigenicity of RCC by repressing E-cadherin, upregulating vimentin, activating MMP9, and invasion activities. In addition, TNF-alpha treatment inhibited glycogen synthase kinase 3 beta (GSK-3 beta) activity through serine-9 phosphorylation mediated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway in RCC cells. Inhibition of PI3K/AKT by LY294002 reactivated GSK-3 beta and suppressed the TNF-alpha-induced EMT of RCC cells. Inactivation of GSK-3 beta by LiCl significantly increased MMP9 activity and EMT of RCC cells. Activation of GSK-3 beta by transduction of constitutively active GSK-3 beta into RCC cells suppressed TNF-alpha-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient GSK-3 beta, in contrast, potentiated EMT, anchorage-independent growth and drastically enhanced tumorigenicity in vivo. Most importantly, a 15-fold inactivation of GSK-3 beta activity, 3-fold decrease of E-cadherin, and 2-fold increase of vimentin were observed in human RCC tumor tissues. These results indicated that inactivation of GSK-3 beta plays a pivotal role in the TNF-alpha-mediated tumorigenesis of RCC. Mol Cancer Res; 10(8); 1109-19. (C) 2012 AACR.