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.