Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype. Issue 12 (21st March 2014)

• Record Type: Journal Article
• Authors: Cougnoux, Antony; Dalmasso, Guillaume; Martinez, Ruben; Buc, Emmanuel; Delmas, Julien; Gibold, Lucie; Sauvanet, Pierre; Darcha, Claude; Déchelotte, Pierre; Bonnet, Mathilde; Pezet, Denis; Wodrich, Harald; Darfeuille-Michaud, Arlette; Bonnet, Richard
• Is Part Of: Gut. Volume 63:Issue 12(2014)
• Page Start: 1932
• Page End: 1942
• Publication Date: 2014-03-21
• Subjects: E. Coli -- Colon Carcinogenesis -- Gene Expression -- DNA Damage -- Cell Proliferation; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2013-305257
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.