Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype
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.
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In several mouse models, other colibactin-producing E. coli have been observed to promote the development of colorectal cancer.
“in several mouse models, other colibactin-producing E. coli have been observed to promote the development of colorectal cancer [125–131]”
From Selection, Comparative Genomics, and Potential Probiotic Features of Escherichia coli 5C, a pks-Negative Strain Isolated from Healthy Infant Donor Feces (2026) · cites this paper as [128]
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- Authors
- Cougnoux, A., Dalmasso, G., Martinez, R., Buc, E., Delmas, J., Gibold, L., Sauvanet, P., Darcha, C., Déchelotte, P., Bonnet, M., Pezet, D., Wodrich, H., Darfeuille-Michaud, A., & Bonnet, R.
- Affiliations
- Inserm (FR)
- Centre National de la Recherche Scientifique (FR)
- Centre Hospitalier Universitaire de Clermont-Ferrand (FR)
- Clermont Université, UMR 1071 Inserm/Université d'Auvergne, Clermont-Ferrand, France
- Corresponding author
- Bonnet, Richard
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2014-03-21
- Volume
- 63
- Issue
- 12
- Pages
- 1932-1942
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- OpenAlex
- W2111725588
- Semantic Scholar
- 15f9aae86af823cd6aad2d6681907d71cc828598
- Cited by
- 486
- References
- 44
- Citations by year
- 2026: 34 · 2025: 35 · 2024: 43 · 2023: 46 · 2022: 54 · 2021: 68 · 2020: 50 · 2019: 37 · 2018: 35 · 2017: 27 · 2016: 25 · 2015: 22 · 2014: 10
- FWCI
- 19.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Ligue Contre le Cancer
- Institut National de la Recherche Agronomique
- Centre Hospitalier Universitaire de Clermont-Ferrand
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Escherichia coli research studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- colibactin, Escherichia coli, pks island, colorectal cancer, tumor growth, cellular senescence, senescence-associated secretory phenotype, hepatocyte growth factor, SENP1, SUMOylation, bacterial carcinogenesis, AOM/DSS model, xenograft models
- MeSH terms
- Animals, Colonic Neoplasms, Cysteine Endopeptidases, Escherichia coli, Humans, Mutagens, Mutation, Neoplasms, Experimental, Nuclear Proteins, Endopeptidases, Peptides, Cellular Senescence, Hepatocyte Growth Factor, Proto-Oncogene Proteins c-met, Mice, Polyketides, Carcinogenesis
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