The MUTYH base excision repair gene protects against inflammation-associated colorectal carcinogenesis

// Francesca Grasso 1, 2 , Serena Di Meo 3, 4 , Gabriele De Luca 5 , Luca Pasquini 5 , Stefania Rossi 5 , Monica Boirivant 6 , Mauro Biffoni 5 , Margherita Bignami 1 , Emma Di Carlo 3, 4 1 Department of Environment and Primary Prevention, Istituto Superiore di Sanita, Rome, Italy 2 Department of Science, University Roma Tre, Rome, Italy 3 Ce.S.I. Biotech, Aging Research Center, “G. d’Annunzio” University Foundation, Chieti, Italy 4 Pathological Anatomy and Molecular Medicine, Department of Medicine and Sciences of Aging, “G. d’Annunzio” University, Chieti, Italy 5 Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanita, Rome, Italy 6 Department of Infectious Parasitic and Immuno-mediated Diseases, Istituto Superiore di Sanita, Rome, Italy Correspondence to: Margherita Bignami, e-mail: margherita.bignami@gmail.com Keywords: MUTYH, azoxymethane, DSS, colorectal cancer, inflammation Received: May 05, 2015      Accepted: June 05, 2015      Published: June 18, 2015 We dedicate this paper to the late Prof. Piero Musiani, whose enthusiasm for science was a continuous inspiration to us. 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.