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Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype
  1. Antony Cougnoux1,2,
  2. Guillaume Dalmasso1,2,
  3. Ruben Martinez3,
  4. Emmanuel Buc1,2,4,
  5. Julien Delmas1,2,5,
  6. Lucie Gibold1,2,5,
  7. Pierre Sauvanet1,2,4,
  8. Claude Darcha6,
  9. Pierre Déchelotte6,
  10. Mathilde Bonnet1,2,
  11. Denis Pezet1,2,4,
  12. Harald Wodrich3,
  13. Arlette Darfeuille-Michaud1,2,
  14. Richard Bonnet1,2,5
  1. 1Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France
  2. 2INRA, USC 2018, Clermont-Ferrand, France
  3. 3Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Université Bordeaux Segalen, Bordeaux, France
  4. 4Service de Chirurgie Digestive, Centre Hospitalier Universitaire, Clermont-Ferrand, France
  5. 5Service de Bactériologie, Centre Hospitalier Universitaire, Clermont-Ferrand, France
  6. 6Servie d'anatomo-pathologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France
  1. Correspondence to Richard Bonnet, CHU, Laboratoire de Bacteriologie, 58 rue Montalembert, Clermont-Ferrand 63000, France; rbonnet{at}chu-clermontferrand.fr

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 (pksE. 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.

  • E. Coli
  • Colon Carcinogenesis
  • Gene Expression
  • DNA Damage
  • Cell Proliferation

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