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Gut Microbes. 2014;5(5):675-80. doi: 10.4161/19490976.2014.969989.

The bacterial genotoxin colibactin promotes colon tumor growth by modifying the tumor microenvironment.

Author information

1
a Clermont Université; Université d'Auvergne; Inserm U1071; INRA USC2018 , Clermont-Ferrand , France.

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.

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

PMID:
25483338
PMCID:
PMC4615906
DOI:
10.4161/19490976.2014.969989
[Indexed for MEDLINE]
Free PMC Article

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