title: Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  These data reveal a new paradigm for carcinogenesis, in which colibactin-induced senescence has an important role.
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France.
authors.forename: Antony
authors.initials: A
authors.lastname: Cougnoux
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dalmasso
authors.affiliation: Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Université Bordeaux Segalen, Bordeaux, France.
authors.forename: Ruben
authors.initials: R
authors.lastname: Martinez
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France Service de Chirurgie Digestive, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Buc
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France Service de Bactériologie, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Delmas
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France Service de Bactériologie, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Gibold
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France Service de Chirurgie Digestive, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sauvanet
authors.affiliation: Servie d'anatomo-pathologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Darcha
authors.affiliation: Servie d'anatomo-pathologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Déchelotte
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Bonnet
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France Service de Chirurgie Digestive, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Pezet
authors.affiliation: Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Université Bordeaux Segalen, Bordeaux, France.
authors.forename: Harald
authors.initials: H
authors.lastname: Wodrich
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France.
authors.forename: Arlette
authors.initials: A
authors.lastname: Darfeuille-Michaud
authors.affiliation: Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France Service de Bactériologie, Centre Hospitalier Universitaire, Clermont-Ferrand, France.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D016922:Cellular Senescence; D003110:Colonic Neoplasms / Q000382:microbiology / Q000473:pathology; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000472:pathogenicity; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D009153:Mutagens; D009154:Mutation; D009374:Neoplasms, Experimental; D009687:Nuclear Proteins / Q000378:metabolism; D010455:Peptides / Q000235:genetics*; D061065:Polyketides; D019859:Proto-Oncogene Proteins c-met
chemical_list: D009153:Mutagens; D009687:Nuclear Proteins; D010455:Peptides; D061065:Polyketides; C569566:colibactin; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse
keywords: Cell Proliferation; Colon Carcinogenesis; DNA Damage; E. Coli; Gene Expression