title: The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis.
abstract: There is growing evidence that the host innate immune system has a critical role in regulating carcinogenesis, but the specific receptors involved and the importance of their interaction with commensal bacteria need to be elucidated. Two major classes of innate immune receptors, the Toll-like receptors and Nod-like receptors, many of which are upstream of nuclear factor-kappaB, are involved in the detection of intestinal bacteria. The Toll-like receptors have been implicated in promoting colon tumorigenesis, but the role of Nod-like receptors in regulating tumorigenesis remains unclear. Using an established mouse model system of colitis-associated colon tumorigenesis, we show that Nod1 deficiency results in the increased development of both colitis-associated and Apc tumor suppressor-related colon tumors. In the absence of Nod1 signaling, there is a greater disruption of the intestinal epithelial cell barrier due to chemically induced injury as manifested by increased surface epithelial apoptosis early on during chemically induced colitis and increased intestinal permeability. The increased intestinal permeability is associated with enhanced inflammatory cytokine production and epithelial cell proliferation in Nod1-deficient mice as compared with wild-type mice. Depletion of the gut microbiota suppressed tumor development in Nod1-deficient mice, thus highlighting a link between the commensal bacteria within the intestine and the host innate immune Nod1 signaling pathway in the regulation inflammation-mediated colon cancer development.
authors.affiliation: Departments of Internal Medicine, Division of Hematology and Oncology, University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109-5938, USA.
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Chen
authors.forename: Michael H
authors.initials: MH
authors.lastname: Shaw
authors.forename: Gloria
authors.initials: G
authors.lastname: Redondo
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000818:Animals; D001397:Azoxymethane; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D016264:Dextran Sulfate; D005260:Female; D017491:Genes, APC; D007113:Immunity, Innate; D007422:Intestines / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053474:Nod1 Signaling Adaptor Protein / Q000172:deficiency / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011971:Receptors, Immunologic / Q000172:deficiency / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms
chemical_list: D018925:Chemokines; D016207:Cytokines; D053474:Nod1 Signaling Adaptor Protein; C507873:Nod1 protein, mouse; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D016264:Dextran Sulfate; D001397:Azoxymethane