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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 (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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