β-catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells

Shilpa Keerthivasan, Katayoun Aghajani, Marei Dose, Luciana Molinero, Mohammad W. Khan, Vysak Venkateswaran, Christopher Weber, Akinola Olumide Emmanuel, Tianjao Sun, David J. Bentrem, Mary Mulcahy, Ali Keshavarzian, Elena M. Ramos, Nichole Blatner, Khashayarsha Khazaie, Fotini Gounari

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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 (TH17) 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 TH17 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 H17 signature genes including RORγt, and promoted T H17-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.

Original languageEnglish (US)
Article number225ra28
JournalScience translational medicine
Volume6
Issue number225
DOIs
StatePublished - Feb 26 2014

ASJC Scopus subject areas

  • General Medicine

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