TY - JOUR T1 - Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype JF - Gut JO - Gut SP - 1932 LP - 1942 DO - 10.1136/gutjnl-2013-305257 VL - 63 IS - 12 AU - Antony Cougnoux AU - Guillaume Dalmasso AU - Ruben Martinez AU - Emmanuel Buc AU - Julien Delmas AU - Lucie Gibold AU - Pierre Sauvanet AU - Claude Darcha AU - Pierre Déchelotte AU - Mathilde Bonnet AU - Denis Pezet AU - Harald Wodrich AU - Arlette Darfeuille-Michaud AU - Richard Bonnet Y1 - 2014/12/01 UR - http://gut.bmj.com/content/63/12/1932.abstract N2 - Background Escherichia coli strains harbouring the pks island (pks+ E. coli) are often seen in human colorectal tumours and have a carcinogenic effect independent of inflammation in an AOM/IL-10−/− (azoxymethane/interleukin) mouse model. Objective To investigate the mechanism sustaining pks+ E. coli-induced carcinogenesis. Method Underlying cell processes were investigated in vitro and in vivo (xenograft model) using intestinal epithelial cells infected by pks+ E. coli or by an isogenic mutant defective for pks (pks− E. coli). The results were supported by data obtained from an AOM/DSS (azoxymethane/dextran sodium sulphate) colon cancer mouse model and from human colon cancer biopsy specimens colonised by pks+ E. coli or pks− E. coli. Results Colibactin-producing E. coli enhanced tumour growth in both xenograft and AOM/DSS models. Growth was sustained by cellular senescence (a direct consequence of small ubiquitin-like modifier (SUMO)-conjugated p53 accumulation), which was accompanied by the production of hepatocyte growth factor (HGF). The underlying mechanisms involve microRNA-20a-5p, which targets SENP1, a key protein regulating p53 deSUMOylation. These results are consistent with the expression of SENP1, microRNA-20a-5p, HGF and phosphorylation of HGF receptor found in human and mouse colon cancers colonised by pks+ E. coli. Conclusion These data reveal a new paradigm for carcinogenesis, in which colibactin-induced senescence has an important role. ER -