Boulard, O., Kirchberger, S., Royston, D.J., Maloy, K.J. & Powrie, F.M. Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation. J. Exp. Med. 209, 1309-1324

Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, England, UK.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/2012; 209(7):1309-24. DOI: 10.1084/jem.20120239
Source: PubMed


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.

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Available from: Stefanie Kirchberger, May 28, 2014
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    • "Immunodeficient RAG−/− mice infected with H. hepaticus and treated with AOM develop invasive colon carcinoma after 3–5 months, at the sites of highest inflammation in the colon and cecum (Fox et al., 2011). This model has also assisted in the identification of a genetic interval on the telomeric part of mouse chromosome 3 designated Hiccs (Helicobacter hepaticus-induced colitis and associated cancer susceptibility), which harbors 8 genes and 5 micro RNAs and confers protection against H. hepaticus-induced chronic colitis and inflammation-driven colon cancer (Boulard et al., 2012). "
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    • "Loci on chromosome 3 have also been shown as strain-dependent contributors to lesions in a Trichuris muris-induced model of colitis (Levison et al. 2013), a G-protein alpha inhibitory 2 chain (Gnai2 -/-) mutant (Borm et al. 2005), T-bet(-/-). Rag2(-/-) double-deficient mice (Ermann et al. 2011), Gpx1(-/-).Gpx2(-/-) double-deficient mice (Esworthy et al. 2011a, b) and a H. hepaticus-induced colitis and colonic tumor model (Boulard et al. 2012). However, these studies focused on a relatively small number of common strains. "
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    • "Exp. cells (Cammarota et al. 2010; Rakhesh et al. 2012). Mice experimental studies help us understand the relationship between genetic predisposition, infection-induced inflammation , neutrophils influx and the development of cancer (Boulard et al. 2012). Understanding the excitation of signaling pathways and the factors regulating cell functioning in the intestinal wall and the environment responsible for these receptor reactions is crucial. "
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