title: The MUTYH base excision repair gene protects against inflammation-associated colorectal carcinogenesis.
abstract: MUTYH DNA glycosylase removes mismatched adenine opposite 7, 8-dihydro-8-oxoguanine (8-oxoG), which is the major mutagenic lesion induced by oxidative stress. Biallelic mutations in MUTYH are associated with MUTYH-Associated polyposis (MAP) and increased risk in colorectal cancer (CRC). We investigated cancer susceptibility associated with MUTYH inactivation in a mouse model of inflammation-dependent carcinogenesis induced by azoxymethane (AOM) and dextran sulphate (DSS). Mutyh-/- mice were more sensitive than wild-type (WT) animals to AOM/DSS toxicity and accumulated DNA 8-oxoG in their gastrointestinal tract. AOM/DSS-induced colonic adenomas were significantly more numerous in Mutyh-/- than in WT animals, and frequently showed a tubulo-villous feature along with high-grade dysplasia and larger size lesions. This condition resulted in a greater propensity to develop adenocarcinomas. The colon of untreated Mutyh-/- mice expressed higher basal levels of pro-inflammatory cytokines GM-CSF and IFNγ, and treatment with AOM/DSS induced an early decrease in circulating CD4+ and CD8+ T lymphocytes and an increase in myeloid-derived suppressor cells (MDSCs). Adenomas from Mutyh-/- mice had a greater infiltrate of Foxp3+ T regulatory cells, granulocytes, macrophages, MDSCs and strong expression of TGF-β-latency-associated peptide and IL6. Our findings indicate that MUTYH loss is associated with an increase in CRC risk, which involves immunosuppression and altered inflammatory response. We propose that the AOM/DSS initiation/promotion protocol in Mutyh-/- mice provides a good model for MAP.
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.|Department of Science, University Roma Tre, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Grasso
authors.affiliation: Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.|Pathological Anatomy and Molecular Medicine, Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Di Meo
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: De Luca
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Pasquini
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Rossi
authors.affiliation: Department of Infectious Parasitic and Immuno-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Boirivant
authors.affiliation: Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Biffoni
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Bignami
authors.affiliation: Ce.S.I. Biotech, Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.|Pathological Anatomy and Molecular Medicine, Department of Medicine and Sciences of Aging, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Di Carlo
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000236:Adenoma / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001397:Azoxymethane; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000378:metabolism; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: C453560:7,8-dihydro-8-oxoguanine; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018836:Inflammation Mediators; D006147:Guanine; D016264:Dextran Sulfate; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; D001397:Azoxymethane
keywords: DSS; MUTYH; azoxymethane; colorectal cancer; inflammation