Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype
Top Cited Papers
- 21 March 2014
- Vol. 63 (12), 1932-1942
- https://doi.org/10.1136/gutjnl-2013-305257
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.Keywords
This publication has 43 references indexed in Scilit:
- A bacterial driver–passenger model for colorectal cancer: beyond the usual suspectsNature Reviews Microbiology, 2012
- Global burden of cancers attributable to infections in 2008: a review and synthetic analysisThe Lancet Oncology, 2012
- Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis -induced colon tumorigenesisProceedings of the National Academy of Sciences, 2011
- Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008International Journal of Cancer, 2010
- Modulation of the Intestinal Microbiota Alters Colitis-Associated Colorectal Cancer SusceptibilityPLOS ONE, 2009
- The cancer genomeNature, 2009
- Cancer epigenomics: DNA methylomes and histone-modification mapsNature Reviews Genetics, 2007
- Extracellular Superoxide Production by Enterococcus faecalis Promotes Chromosomal Instability in Mammalian CellsGastroenterology, 2007
- Bacterial toxins and cancer — a case to answer?Nature Reviews Microbiology, 2005
- A genetic model for colorectal tumorigenesisCell, 1990