期刊
GUT MICROBES
卷 5, 期 5, 页码 675-680出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/19490976.2014.969989
关键词
colibactin; colorectal cancer; Escherichia coli; microbiota; toxin; micro-RNA; SENP1; SUMO
资金
- Ministere de la Recherche et de la Technologie
- Institut National de la Sante et de la Recherche Medicale (UMR Inserm) [U1071]
- l'Institut National de la Recherche Agronomique (USC-2018)
- Ligue Contre le Cancer
- Center Hospitalier Regional Universitaire de Clermont-Ferrand, France
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. colt) 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. coll. 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.
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