Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation

Boulard, O., Kirchberger, S., Royston, D. J., Maloy, K. J. and Powrie, F. M. (2012) Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation. Journal of Experimental Medicine, 209(7), pp. 1309-1324. (doi: 10.1084/jem.20120239) (PMID:22734048) (PMCID:PMC3405508)

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Abstract

Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer. Recent association studies have highlighted the role of genetic predisposition in the etiology of colitis and started to unravel its complexity. However, the genetic factors influencing the progression from colon inflammation to tumorigenesis are not known. We report the identification of a genetic interval Hiccs that regulates Helicobacter hepaticus–induced colitis and associated cancer susceptibility in a 129.RAG−/− mouse model. The 1.7-Mb congenic interval on chromosome 3, containing eight genes and five microRNAs, renders susceptible mice resistant to colitis and reduces tumor incidence and multiplicity. Bone marrow chimera experiments showed that resistance is conferred by the hematopoietic compartment. Moreover, the Hiccs locus controls the induction of the innate inflammatory response by regulating cytokine expression and granulocyte recruitment by Thy1+ innate lymphoid cells. Using a tumor-promoting model combining chronic Helicobacter hepaticus infection and the carcinogen azoxymethane, we found that Hiccs also regulates the frequency of colitis-associated neoplasia. Our study highlights the importance of innate immune cells and their genetic configuration in driving progression from inflammation toward cancer and opens the door for analysis of these pathways in human inflammatory disorders and associated cancers.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Maloy, Professor Kevin
Authors: Boulard, O., Kirchberger, S., Royston, D. J., Maloy, K. J., and Powrie, F. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Experimental Medicine
Publisher:Rockefeller University Press
ISSN:0022-1007
ISSN (Online):1540-9538
Published Online:25 June 2012

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