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Genetic locus controls bacteria-induced colitis and associated cancer
▸ Boulard O, Kirchberger S, Royston DJ, et al. Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation. J Exp Med 2012;209:1309–24.
While many genetic studies have identified pathways that contribute to inflammatory bowel disease (IBD) susceptibility, the genetic factors involved in progression from colon inflammation to colitis-associated colorectal cancer (CAC) are not known. In this study by Boulard et al, the authors identify a major susceptibility locus for Helicobacter hepaticus-induced innate colitis and CAC in the 129S6.Rag−/− mouse strain. The locus, designated Hiccs, renders susceptible mice resistant to colitis and reduces colon tumour formation. Hiccs was mapped to a 1.71-Mb interval on chromosome 3, and found to include altered expression of three genes and differences in non-synonymous single nucleotide polymorphisms between resistant and susceptible strains. Analysis of colonic lamina propria leukocytes showed that resistance to colitis correlates with reduced secretion of pro-inflammatory cytokines. Bone marrow chimaera experiments demonstrated that Hiccs acts specifically in innate haematopoietic cells to confer resistance to H hepaticus-induced colitis. Innate inflammation without proper immune regulation plays a key role in inflammation-induced cancer. In order to identify how Hiccs controls the early inflammatory response, kinetic analyses of the innate response following H hepaticus infection were performed. Inflammatory cytokine production (TNF, IL-1β, and IFN-γ) and granulocyte recruitment driven by innate lymphoid cells are both controlled by Hiccs. The authors used a novel tumour induction protocol combining administration of the carcinogen azoxymethane with H hepaticus infection to explore whether the Hiccs locus is involved in CAC development. The Hiccs locus dramatically reduced frequency of colitis-associated invasive adenocarcinoma from 75% to 29%. This study along with further research on molecular pathways involved in increasing susceptibility to colitis and CAC could promote new insights …
Contributors Dr Miranda Hanson, Dr Prakash Ramachandran, Dr Paul Lochhead, Dr Jonathan MacDonald, Dr Ashis Mukhopadhya, Dr Mairi McLean.
Competing interests None.
Journals reviewed Journal of Experimental Medicine, Proceedings of the National Academy of Science USA, Nature, Gastrointestinal Endoscopy, Hepatology, Gastroenterology.
Provenance and peer review Not commissioned; internally peer reviewed.
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