Cheng Sherman M, Xing Bing, Li James C B, Cheung Benny K W, Lau Allan S Y
Immunology Research Laboratory, Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
Int J Cancer. 2007 Sep 15;121(6):1190-6. doi: 10.1002/ijc.22729.
Induction of proinflammatory cytokines in response to malignant cells is an integral component of immune response to control tumor development. However, recent evidences have suggested that tumor cells may evade the immune system and exploit inflammatory responses to enhance its own growth. An exemplary example is the highly invasive and tumor necrosis factor (TNF)alpha-resistant glioblastoma, whose growth is associated with TNFalpha expression. We thus examined whether the tumor takes advantage of TNFalpha overexpression to enhance its invasiveness. To delineate the contribution of inflammation in tumor migration, we demonstrated that the role of proinflammatory cytokines on matrix metalloproteinases-3 (MMP-3) expression, and its consequent effects on the invasiveness of a human glioma cell-line, T98G. By using Matrigel Invasion Chamber, T98G cell migration was significantly enhanced in response to TNFalpha. In contrast, interferon-gamma (IFN gamma) reduced both basal and TNFalpha-enhanced cell invasion. To investigate the mechanisms involved, we demonstrated that TNFalpha upregulated mRNA and protein expression of MMP-3 in T98G cells, whereas IFN gamma downregulated the MMP-3 expression. The role of MMP-3 in glioma invasiveness was further confirmed by transfecting MMP-3 siRNA in T98G to abrogate the TNFalpha-enhanced cell invasion. To delineate the mechanisms further, we showed that IFN gamma exerts an inhibitory effect on the binding of TNFalpha-activated Ets-1 and NF kappa B to their respective enhancer elements found in MMP-3 promoter. In summary, our results indicated that TNFalpha enhances the invasiveness of T98G glioma cells through MMP-3 induction, and such enhancement of cell migration can be inhibited by IFN gamma.
对恶性细胞产生促炎细胞因子的诱导是控制肿瘤发展的免疫反应的一个重要组成部分。然而，最近的证据表明肿瘤细胞可能逃避免疫系统并利用炎症反应来促进自身生长。一个典型的例子是具有高度侵袭性且对肿瘤坏死因子（TNF）α耐药的胶质母细胞瘤，其生长与TNFα的表达相关。因此，我们研究了肿瘤是否利用TNFα的过表达来增强其侵袭性。为了阐明炎症在肿瘤迁移中的作用，我们证明了促炎细胞因子对基质金属蛋白酶-3（MMP-3）表达的作用，以及其对人胶质瘤细胞系T98G侵袭性的后续影响。通过使用基质胶侵袭小室，T98G细胞对TNFα的反应迁移显著增强。相比之下，干扰素-γ（IFNγ）降低了基础水平以及TNFα增强的细胞侵袭。为了研究其中涉及的机制，我们证明TNFα上调了T98G细胞中MMP-3的mRNA和蛋白表达，而IFNγ下调了MMP-3的表达。通过在T98G细胞中转染MMP-3 siRNA以消除TNFα增强的细胞侵袭，进一步证实了MMP-3在胶质瘤侵袭性中的作用。为了进一步阐明机制，我们表明IFNγ对TNFα激活的Ets-1和核因子κB与MMP-3启动子中各自增强子元件的结合具有抑制作用。总之，我们的结果表明TNFα通过诱导MMP-3增强了T98G胶质瘤细胞的侵袭性，而这种细胞迁移的增强可被IFNγ抑制。
