Antony Cougnoux1, Guillaume Dalmasso1, Ruben Martinez2, Emmanuel Buc3, Julien Delmas4, Lucie Gibold4, Pierre Sauvanet3, Claude Darcha5, Pierre Déchelotte5, Mathilde Bonnet1, Denis Pezet3, Harald Wodrich2, Arlette Darfeuille-Michaud1, Richard Bonnet4. 1. Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France INRA, USC 2018, Clermont-Ferrand, France. 2. Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Université Bordeaux Segalen, Bordeaux, France. 3. 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. 4. 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. 5. Servie d'anatomo-pathologie, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
BACKGROUND:Escherichia coli strains harbouring the pks island (pks+ E. coli) are often seen in humancolorectal 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 cancermouse model and from humancolon 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 mousecolon cancers colonised by pks+ E. coli. CONCLUSION: These data reveal a new paradigm for carcinogenesis, in which colibactin-induced senescence has an important role. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Entities:
Keywords:
Cell Proliferation; Colon Carcinogenesis; DNA Damage; E. Coli; Gene Expression
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