The MUTYH base excision repair gene protects against inflammation-associated colorectal carcinogenesis
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Francesca Grasso1,2, Serena Di Meo3,4, Gabriele De Luca5, Luca Pasquini5, Stefania Rossi5, Monica Boirivant6, Mauro Biffoni5, Margherita Bignami1, Emma Di Carlo3,4
1Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Rome, Italy
2Department of Science, University Roma Tre, Rome, Italy
3Ce.S.I. Biotech, Aging Research Center, “G. d’Annunzio” University Foundation, Chieti, Italy
4Pathological Anatomy and Molecular Medicine, Department of Medicine and Sciences of Aging, “G. d’Annunzio” University, Chieti, Italy
5Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
6Department of Infectious Parasitic and Immuno-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy
Margherita Bignami, e-mail: [email protected]
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.
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.
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