Yan Yan, Li Jingxia, Ouyang Weiming, Ma Qian, Hu Yu, Zhang Dongyun, Ding Jin, Qu Qingshan, Subbaramaiah Kotha, Huang Chuanshu
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.
J Cell Sci. 2006 Jul 15;119(Pt 14):2985-94. doi: 10.1242/jcs.03014. Epub 2006 Jun 27.
NFAT family is recognized as a transcription factor for inflammation regulation by inducing the expression of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), the key mediator of inflammation, which was reported to induce cell transformation in mouse epidermal Cl41 cells. In this study, we demonstrated that TNF-alpha was able to induce NFAT activation, as well as the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). The induction of COX-2 by TNF-alpha was abolished by knockdown of NFAT3 with its siRNA, while the induction of iNOS was not effected. Moreover, TNF-alpha-induced anchorage-independent cell growth was significantly inhibited by NFAT3 siRNA and cyclosporine A, a chemical inhibitor for the calcineurin/NFAT pathway, which suggests the importance of NFAT3 in regulating TNF-alpha-induced anchorage-independent cell growth. Consequently, impairment of COX-2 by its siRNA or selective inhibitor also inhibited TNF-alpha-induced anchorage-independent cell growth. Taken together, our results indicate that NFAT3 plays an important role in the regulation of TNF-alpha-induced anchorage-independent cell growth, at least partially, by inducing COX-2 expression in Cl41 cells. These findings suggest that NFAT3/cyclooxygenase-2 act as a link between inflammation and carcinogenesis by being involved in the tumor promotion stage.
NFAT家族被认为是一种通过诱导促炎细胞因子表达来调节炎症的转录因子，这些促炎细胞因子如肿瘤坏死因子-α（TNF-α），是炎症的关键介质，据报道其可诱导小鼠表皮Cl41细胞发生细胞转化。在本研究中，我们证明TNF-α能够诱导NFAT激活，以及环氧合酶-2（COX-2）和诱导型一氧化氮合酶（iNOS）的表达。用其siRNA敲低NFAT3可消除TNF-α对COX-2的诱导作用，而对iNOS的诱导作用没有影响。此外，NFAT3 siRNA和环孢素A（一种钙调神经磷酸酶/NFAT途径的化学抑制剂）可显著抑制TNF-α诱导的不依赖贴壁细胞生长，这表明NFAT3在调节TNF-α诱导的不依赖贴壁细胞生长中具有重要作用。因此，用COX-2的siRNA或选择性抑制剂对其进行抑制也可抑制TNF-α诱导的不依赖贴壁细胞生长。综上所述，我们的结果表明NFAT3在调节TNF-α诱导的不依赖贴壁细胞生长中起重要作用，至少部分是通过在Cl41细胞中诱导COX-2表达来实现的。这些发现表明NFAT3/环氧合酶-2通过参与肿瘤促进阶段，在炎症和致癌作用之间起到了联系作用。
