Transcription Factor NFATc2 Controls the Emergence of Colon Cancer Associated with IL-6–Dependent Colitis

Abstract

NFAT transcription factors control T-cell activation and function. Specifically, the transcription factor NFATc2 affects the regulation of cell differentiation and growth and plays a critical role in the development of colonic inflammation. Here, we used an experimental model of colitis-associated colorectal carcinoma to investigate the contribution of NFATc2 to the promotion of colonic tumors. Compared with wild-type animals that readily presented with multiple colon tumors, NFATc2-deficient mice were protected from tumor development. This observed decrease in colonic tumor progression was associated with reduced endoscopic inflammation, increased apoptosis of lamina propria T lymphocytes, and significantly reduced levels of the critical proinflammatory cytokines interleukin (IL)-21 and IL-6. Administration of hyper IL-6 abrogated protection from tumor progression in NFATc2-knockout mice and restored tumor incidence to control levels. Taken together, our findings highlight a pivotal role for NFATc2 in the establishment of inflammation-associated colorectal tumors mediated by control of IL-6 expression. Cancer Res; 72(17); 4340-50. Ó2012 AACR.

Nfatc2 and Tob1 Have Non-Overlapping Function in T Cell Negative Regulation and Tumorigenesis

“…Our experiments support previous observations regarding the context-dependent function of Nfatc2 and Tob1 in different genetic backgrounds [14], [30], [32], [33]. Nfatc2 KO mice in a mixed B6×129/SvJ background showed splenomegaly with reduced thresholds for T-cell activation, and these observations were faithfully replicated in our studies of the same mice [24].…”

“…For example, Nfatc2 KO mice are resistant to suppression of the G0 to G1 transition by nicotine [9], Nfatc2/Nfatc3-doubly deficient CD4 + Tconv cells are refractory to the effects of WT Treg cells in vitro [10], Nfatc2-deficient T cells resist tumor-induced anergy and promote tumor rejection [11], and mice with T cells harboring a hyperactivatable form of Nfatc2 show attenuated autoimmune responses to myelin basic protein [12]. However, the observation that oxazolone-induced ulcerative colitis and progression to colon cancer are attenuated in Nfatc2 KO mice due to ineffective production of IL-6 [13], [14] suggests that the function of Nfatc2 is not uniquely to repress cell cycle or lymphocyte activation, but rather, it can act as a more general modulator of inflammation and even as an oncogene in non-lymphoid cells.…”

Transcription Factor NFAT1 Activates the mdm2 Oncogene Independent of p53

“…In the same report, transgenic mice lacking NFAT1 were shown to have more and larger bronchioalveolar adenocarcinoma than wild-type littermates, which may be associated with the immunomodulatory function of NFAT1. In contrary, Gerlach et al (41) suggest that NFAT1-deficient mice are protected from colitis-associated colon cancer development compared with wild-type animals. In brief, NFAT1 expression and activation may be tumor specific and stage-dependent.…”

IL-21 and Related Diseases

“…Treated with neutralizing IL-21 antibody, the wild-type mice developed fewer smaller tumors than mice treated with a control antibody [82,84]. NFATc2-deficient mice significantly reduced tumor incidence due to the low levels of IL-21 and IL-6 secretion, leading to the reduction of endoscopic inflammation, increase of lamina propria T lymphocytes [86]. It demonstrates that NFAT transcription factors mediate T-cell activations and functions.…”