Mol Cancer Res：TNF-α诱导肾细胞癌上皮间质转化

肿瘤坏死因子的产生-α（TNF-α）主要由活化的单核/巨噬细胞产生，能杀伤和抑制肿瘤细胞的细胞因子。促进中性粒细胞吞噬，抗感染，引起发热，诱导肝细胞急性期蛋白合成，促进髓样白血病细胞向巨噬细胞分化，促进细胞增殖和分化，是重要的炎症介质，并参与某些自身免疫病的病理损伤。

TNF-α是一种具有抗肿瘤特性的细胞因子。而相比之下，肿瘤细胞或基质细胞低剂量地、缓慢生成肿瘤坏死因子可能会促进肿瘤生长和转移。

在肾细胞癌（RCC）患者血清中，TNF-α的含量显著升高。在最新的研究中，科学家证实肿瘤坏死因子-α通过抑制E-钙粘素，上调波形蛋白，激活MMP9等肿瘤侵袭活性，诱导上皮间质转化（EMT）促进肾癌细胞株的致瘤性。

此外，肿瘤坏死因子-α通过丝氨酸磷酸化介导的PI3K/AKT通路抑制肾细胞糖原合酶激酶3β（GSK-3β）的活性。用LY294002抑制剂阻断PI3K/AKT会重新激活GSK-3β，进而抑制肾细胞TNF-α诱导的EMT。

而利用LiCl使得GSK-3β灭活能显著增加肾细胞MMP9的活性，EMT也加剧。GSK-3β的激活抑制TNF-α介导的软琼脂上肿瘤细胞的生长以及裸鼠RCC的致瘤性。最重要的是在人肾癌肿瘤组织中GSK-3β的活性足足降低了15倍，E-钙粘素的活性降低了3倍，而波形蛋白的表达增加了2倍。这些结果表明，GSK-3β的失活在TNF-α介导的RCC成瘤过程中起着举足轻重的作用。

doi:10.1158/1541-7786.MCR-12-0160
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TNF-α induces epithelial-mesenchymal transition of renal cell carcinoma cells via a GSK3β-dependent mechanism

Ming-Yi Ho, Shye-Jye Tang, Mei-Jen Chuang, Tai-Lung Cha, Jing-Yao Li, Guang-Huan Sun, and Kuang-Hui Sun*

Tumor necrosis factor α (TNF-α) is a cytokine with antitumorigenic property. In contrast, low dose, chronic TNF-α production by tumor cells or stromal cells may promote tumor growth and metastasis. Serum levels of TNF-α are significantly elevated in renal cell carcinoma (RCC) patients. Here, we demonstrate that TNF-α induced epithelial-mesenchymal transition (EMT) and promoted tumorigenicity of RCC by repressing E-cadherin, up-regulating vimentin, activating MMP9, and invasion activities. In addition, TNF-α treatment inhibited glycogen synthase kinase 3β (GSK-3β) 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-3β and suppressed the TNF-α-induced EMT of RCC cells. Inactivation of GSK-3β by LiCl significantly increased MMP9 activity and EMT of RCC cells. Activation of GSK-3β by transduction of constitutively active GSK-3β into RCC cells suppressed TNF-α-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient GSK-3β, in contrast, potentiated EMT, anchorage-independent growth and drastically enhanced tumorigenicity in vivo. Most importantly, a 15-fold inactivation of GSK-3β activity, 3-fold decrease of E-cadherin, and 2-fold increase of vimentin were observed in human RCC tumor tissues. These results indicate that inactivation of GSK-3β plays a pivotal role in the TNF-α-mediated tumorigenesis of RCC.