1. β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells.
- Author
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Keerthivasan S, Aghajani K, Dose M, Molinero L, Khan MW, Venkateswaran V, Weber C, Emmanuel AO, Sun T, Bentrem DJ, Mulcahy M, Keshavarzian A, Ramos EM, Blatner N, Khazaie K, and Gounari F
- Subjects
- Animals, Binding Sites, CD4-Positive T-Lymphocytes immunology, Cell Line, Tumor, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic immunology, Cell Transformation, Neoplastic metabolism, Chromatin Assembly and Disassembly, Colitis genetics, Colitis immunology, Colitis pathology, Colon immunology, Colon pathology, Colonic Neoplasms genetics, Colonic Neoplasms immunology, Colonic Neoplasms pathology, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Genes, APC, Hepatocyte Nuclear Factor 1-alpha, Humans, Lymphocyte Activation, Lymphocytes, Tumor-Infiltrating immunology, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nuclear Receptor Subfamily 1, Group F, Member 3 genetics, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, T Cell Transcription Factor 1 genetics, T Cell Transcription Factor 1 metabolism, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Th17 Cells immunology, Th17 Cells metabolism, Wnt Signaling Pathway, beta Catenin genetics, CD4-Positive T-Lymphocytes metabolism, Colitis metabolism, Colon metabolism, Colonic Neoplasms metabolism, Inflammation Mediators metabolism, Lymphocytes, Tumor-Infiltrating metabolism, beta Catenin metabolism
- Abstract
The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORγt (retinoic acid-related orphan receptor-γt), the signature transcription factor of T(H)17 cells. We report that Wnt/β-catenin signaling in T cells promotes expression of RORγt. Expression of β-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of β-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORγt, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/β-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer.
- Published
- 2014
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