Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype.
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.
['Cougnoux|Antony|A|', 'Dalmasso|Guillaume|G|', 'Martinez|Ruben|R|', 'Buc|Emmanuel|E|', 'Delmas|Julien|J|', 'Gibold|Lucie|L|', 'Sauvanet|Pierre|P|', 'Darcha|Claude|C|', 'Déchelotte|Pierre|P|', 'Bonnet|Mathilde|M|', 'Pezet|Denis|D|', 'Wodrich|Harald|H|', 'Darfeuille-Michaud|Arlette|A|', 'Bonnet|Richard|R|']
D000818:Animals D063646:Carcinogenesis D016922:Cellular Senescence D003110:Colonic Neoplasms D003546:Cysteine Endopeptidases D010450:Endopeptidases D004926:Escherichia coli D017228:Hepatocyte Growth Factor D006801:Humans D051379:Mice D009153:Mutagens D009154:Mutation D009374:Neoplasms, Experimental D009687:Nuclear Proteins D010455:Peptides D061065:Polyketides D019859:Proto-Oncogene Proteins c-met
E. Coli Cell Proliferation Colon Carcinogenesis DNA Damage Gene Expression