Caspase-11 regulates the tumour suppressor function of STAT1 in a murine model of colitis-associated carcinogenesis
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2019Author:
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Flood, B., Manils, J., Nulty, C., Flis, E., Kenealy, S., Barber, G., Fay, J., Mills, K.H.G., Kay, E.W., & Creagh, E.M. Caspase-11 regulates the tumour suppressor function of STAT1 in a murine model of colitis-associated carcinogenesis, Oncogene, 38, 14, 2019, 2658-2674Download Item:
Abstract:
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 pro-inflammatory cytokines IL-1β 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−/− 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-1βproduction is more significantly impaired inCasp11−/− colons during established CAC. We identify defective STAT1 activation in Casp11−/− colons during disease progression, and show that IL-1β 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-11and the non-canonical inflammasome during CAC, and suggest a critical role for caspase-11, linking IL-1
β and STAT1 signalling pathways.
Sponsor
Grant Number
Enterprise Ireland
CF-2015 0061P
Marie Curie
721906
Science Foundation Ireland (SFI)
12/IP/1400
Author's Homepage:
http://people.tcd.ie/ecreaghhttp://people.tcd.ie/millsk
Author: Creagh, Emma; Mills, Kingston; Flood, Brie; Manils, Joan; Nulty, Ciara; Flis, Ewelina; Kenealy, Sinead; Barber, Gillian; Fay, Joanna; Kay, Elaine
Sponsor:
Enterprise IrelandMarie Curie
Science Foundation Ireland (SFI)
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Oncogene;38;
14;
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Full text availableKeywords:
Molecular Biology, Colon cancer, InflammationSubject (TCD):
Cancer , Immunology, Inflammation & Infection , COLORECTAL CANCERDOI:
http://dx.doi.org/10.1038/s41388-018-0613-5Source URI:
Springer Nature SharingISSN:
0950-9232Metadata
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