title: β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells.
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.
authors.affiliation: Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Keerthivasan
authors.forename: Katayoun
authors.initials: K
authors.lastname: Aghajani
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.forename: Luciana
authors.initials: L
authors.lastname: Molinero
authors.forename: Mohammad W
authors.initials: MW
authors.lastname: Khan
authors.forename: Vysak
authors.initials: V
authors.lastname: Venkateswaran
authors.forename: Christopher
authors.initials: C
authors.lastname: Weber
authors.forename: Akinola Olumide
authors.initials: AO
authors.lastname: Emmanuel
authors.forename: Tianjao
authors.initials: T
authors.lastname: Sun
authors.forename: David J
authors.initials: DJ
authors.lastname: Bentrem
authors.forename: Mary
authors.initials: M
authors.lastname: Mulcahy
authors.forename: Ali
authors.initials: A
authors.lastname: Keshavarzian
authors.forename: Elena M
authors.initials: EM
authors.lastname: Ramos
authors.forename: Nichole
authors.initials: N
authors.lastname: Blatner
authors.forename: Khashayarsha
authors.initials: K
authors.lastname: Khazaie
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
mesh_terms: D000818:Animals; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D018836:Inflammation Mediators; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; C499308:Rag2 protein, mouse; C539901:Rorc protein, mouse; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D051176:beta Catenin