TY - JOUR T1 - ZEB1 promotes inflammation and progression towards inflammation-driven carcinoma through repression of the DNA repair glycosylase MPG in epithelial cells JF - Gut JO - Gut DO - 10.1136/gutjnl-2018-317294 SP - gutjnl-2018-317294 AU - Oriol de Barrios AU - Lidia Sanchez-Moral AU - Marlies Cortés AU - Chiara Ninfali AU - Nuria Profitós-Pelejà AU - MC Martínez-Campanario AU - Laura Siles AU - Rosa del Campo AU - María Jesús Fernández-Aceñero AU - Douglas S Darling AU - Antoni Castells AU - Joan Maurel AU - Azucena Salas AU - Douglas C Dean AU - Antonio Postigo Y1 - 2019/09/06 UR - http://gut.bmj.com/content/early/2019/09/05/gutjnl-2018-317294.abstract N2 - Objective Chronic inflammation is a risk factor in colorectal cancer (CRC) and reactive oxygen species (ROS) released by the inflamed stroma elicit DNA damage in epithelial cells. We sought to identify new drivers of ulcerative colitis (UC) and inflammatory CRC.Design The study uses samples from patients with UC, mouse models of colitis and CRC and mice deficient for the epithelial-to-mesenchymal transition factor ZEB1 and the DNA repair glycosylase N-methyl-purine glycosylase (MPG). Samples were analysed by immunostaining, qRT-PCR, chromatin immunoprecipitation assays, microbiota next-generation sequencing and ROS determination.Results ZEB1 was induced in the colonic epithelium of UC and of mouse models of colitis. Compared with wild-type counterparts, Zeb1-deficient mice were partially protected from experimental colitis and, in a model of inflammatory CRC, they developed fewer tumours and exhibited lower levels of DNA damage (8-oxo-dG) and higher expression of MPG. Knockdown of ZEB1 in CRC cells inhibited 8-oxo-dG induction by oxidative stress (H2O2) and inflammatory cytokines (interleukin (IL)1β). ZEB1 bound directly to the MPG promoter whose expression inhibited. This molecular mechanism was validated at the genetic level and the crossing of Zeb1-deficient and Mpg-deficient mice reverted the reduced inflammation and tumourigenesis in the former. ZEB1 expression in CRC cells induced ROS and IL1β production by macrophages that, in turn, lowered MPG in CRC cells thus amplifying a positive loop between both cells to promote DNA damage and inhibit DNA repair.Conclusions ZEB1 promotes colitis and inflammatory CRC through the inhibition of MPG in epithelial cells, thus offering new therapeutic strategies to modulate inflammation and inflammatory cancer. ER -