腫瘤壞死因子的產(chǎn)生-α（TNF-α）主要由活化的單核/巨噬細(xì)胞產(chǎn)生,，能殺傷和抑制腫瘤細(xì)胞的細(xì)胞因子,。促進(jìn)中性粒細(xì)胞吞噬,，抗感染,，引起發(fā)熱,，誘導(dǎo)肝細(xì)胞急性期蛋白合成,，促進(jìn)髓樣白血病細(xì)胞向巨噬細(xì)胞分化，促進(jìn)細(xì)胞增殖和分化,，是重要的炎癥介質(zhì),，并參與某些自身免疫病的病理損傷。
TNF-α是一種具有抗腫瘤特性的細(xì)胞因子,。而相比之下,，腫瘤細(xì)胞或基質(zhì)細(xì)胞低劑量地、緩慢生成腫瘤壞死因子可能會(huì)促進(jìn)腫瘤生長和轉(zhuǎn)移,。
在腎細(xì)胞癌（RCC）患者血清中,，TNF-α的含量顯著升高。在最新的研究中,，科學(xué)家證實(shí)腫瘤壞死因子-α通過抑制E-鈣粘素,，上調(diào)波形蛋白，激活MMP9等腫瘤侵襲活性,，誘導(dǎo)上皮間質(zhì)轉(zhuǎn)化（EMT）促進(jìn)腎癌細(xì)胞株的致瘤性,。
此外，腫瘤壞死因子-α通過絲氨酸磷酸化介導(dǎo)的PI3K/AKT通路抑制腎細(xì)胞糖原合酶激酶3β（GSK-3β）的活性,。用LY294002抑制劑阻斷PI3K/AKT會(huì)重新激活GSK-3β,，進(jìn)而抑制腎細(xì)胞TNF-α誘導(dǎo)的EMT。
而利用LiCl使得GSK-3β滅活能顯著增加腎細(xì)胞MMP9的活性,，EMT也加劇,。GSK-3β的激活抑制TNF-α介導(dǎo)的軟瓊脂上腫瘤細(xì)胞的生長以及裸鼠RCC的致瘤性。最重要的是在人腎癌腫瘤組織中GSK-3β的活性足足降低了15倍,，E-鈣粘素的活性降低了3倍,，而波形蛋白的表達(dá)增加了2倍。這些結(jié)果表明,，GSK-3β的失活在TNF-α介導(dǎo)的RCC成瘤過程中起著舉足輕重的作用,。(生物谷：Bioon.com）
doi:10.1158/1541-7786.MCR-12-0160
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PMID:
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.
