4.8 Article

Caspase-11 regulates the tumour suppressor function of STAT1 in a murine model of colitis-associated carcinogenesis

Journal

ONCOGENE
Volume 38, Issue 14, Pages 2658-2674

Publisher

SPRINGERNATURE
DOI: 10.1038/s41388-018-0613-5

Keywords

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Funding

  1. Enterprise Ireland [CF-2015-0061P]
  2. Government of Ireland PRTLI PhD programme [201921, 12259]
  3. EU [721906]
  4. SFI Investigator programme [12/IP/1400]
  5. Science Foundation Ireland (SFI) [12/IP/1400] Funding Source: Science Foundation Ireland (SFI)
  6. Marie Curie Actions (MSCA) [721906] Funding Source: Marie Curie Actions (MSCA)

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Murine inflammatory caspase-11 has an important role in intestinal epithelial inflammation and barrier function. Activation of the non-canonical inflammasome, mediated by caspase-11, serves as a regulatory pathway for the production of the proinflammatory cytokines IL-1 beta and IL-18, and has a key role in pyroptotic cell death. We have previously demonstrated a protective role for caspase-11 during dextran sulphate sodium (DSS)-induced colitis, however the importance of caspase-11 during colorectal tumour development remains unclear. Here, we show that Casp11(-1-) mice are highly susceptible to the azoxymethane (AOM)-DSS model of colitis-associated cancer (CAC), compared to their wild type (WT) littermates. We show that deficient IL-18 production occurs at initial inflammation stages of disease, and that IL-1 beta production is more significantly impaired in Casp11(-1-) colons during established CAC. We identify defective STAT1 activation in Casp11(-)(1-) colons during disease progression, and show that IL-1 beta signalling induces caspase-11 expression and STAT1 activation in primary murine macrophages and intestinal epithelial cells. These findings uncover an anti-tumour role for the caspase-11 and the non-canonical inflammasome during CAC, and suggest a critical role for caspase-11, linking IL-1 beta and STAT1 signalling pathways.

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