title: The bacterial genotoxin colibactin promotes colon tumor growth by modifying the tumor microenvironment.
abstract: The gut microbiota is suspected to promote colorectal cancer (CRC). Escherichia coli are more frequently found in CCR biopsies than in healthy mucosa; furthermore, the majority of mucosa-associated E. coli isolated from CCR harbors the pks genomic island (pks+ E. coli) that is responsible for the synthesis of colibactin, a genotoxic compound. We have recently reported that transient contact of a few malignant cells with colibactin-producing E. coli increases tumor growth in a xenograft mouse model. Growth is sustained by cellular senescence that is accompanied by the production of growth factors. We demonstrated that cellular senescence is a consequence of the pks+ E. coli-induced alteration of p53 SUMOylation, an essential post-translational modification in eukaryotic cells. The underlying mechanisms for this process involve the induction of miR-20a-5p expression, which targets SENP1, a key protein in the regulation of the SUMOylation process. These results are consistent with the expression of SENP1, miR-20a-5p and growth factors that are observed in a CRC mouse model and in human CCR biopsies colonized by pks+ E. coli. Overall, the data reveal a new paradigm for carcinogenesis in which pks+ E. coli infection induces cellular senescence characterized by the production of growth factors that promote the proliferation of uninfected cells and, subsequently, tumor growth.
authors.affiliation: a Clermont Université; Université d'Auvergne; Inserm U1071; INRA USC2018 , Clermont-Ferrand , France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Dalmasso
authors.forename: Antony
authors.initials: A
authors.lastname: Cougnoux
authors.forename: Julien
authors.initials: J
authors.lastname: Delmas
authors.forename: Arlette
authors.initials: A
authors.lastname: Darfeuille-Michaud
authors.forename: Richard
authors.initials: R
authors.lastname: Bonnet
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000473:pathology*; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000254:growth & development*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008954:Models, Biological; D009153:Mutagens / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D061065:Polyketides / Q000378:metabolism*; D058207:Sumoylation; D059016:Tumor Microenvironment / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D035683:MicroRNAs; C532375:Mirn20 microRNA, mouse; D009153:Mutagens; D010455:Peptides; D061065:Polyketides; D016159:Tumor Suppressor Protein p53; C569566:colibactin; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C501974:Senp1 protein, mouse
keywords: AOM, azoxymethane; CM, conditioned medium; CRC, colorectal cancer; DSS, dextran sodium sulfate; Escherichia coli, microbiota; MOI, multiplicity of infection; SA-β-gal, senescence-associated β-galactosidase; SASP, senescence-associated secretory phenotype; SENP1; SUMO; colibactin; colorectal cancer; miR, microRNA; pks+ E. coli, colibactin-producing E. coli; pks- E. coli, isogenic mutant of pks+ E. coli deficient for colibactin production; toxin, microRNA