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

被引:53
作者
Gerlach, Katharina [1 ]
Daniel, Carolin [2 ]
Lehr, Hans A. [5 ]
Nikolaev, Alexei [3 ]
Gerlach, Thomas [1 ]
Atreya, Raja [1 ]
Rose-John, Stefan [4 ]
Neurath, Markus F. [1 ]
Weigmann, Benno [1 ]
机构
[1] Univ Erlangen Nurnberg, Med Clin 1, D-91052 Erlangen, Germany
[2] Helmholtz Zentrum Muenchen, Diabet Res Inst, Neuherberg, Germany
[3] Johannes Gutenberg Univ Mainz, Inst Mol Med, Mainz, Germany
[4] Univ Kiel, Inst Biochem, D-2300 Kiel, Germany
[5] Univ Lausanne, Inst Univ Pathol, CH-1015 Lausanne, Switzerland
关键词
CHRONIC INTESTINAL INFLAMMATION; T-CELL-ACTIVATION; COLORECTAL-CANCER; ULCERATIVE-COLITIS; SIGNALING PATHWAY; TUMOR PROGRESSION; NUCLEAR FACTOR; BOWEL-DISEASE; IN-VIVO; EXPRESSION;
D O I
10.1158/0008-5472.CAN-11-4155
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 proin-flammatory 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. (c) 2012 AACR.
引用
收藏
页码:4340 / 4350
页数:11
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