Attaching and Effacing Escherichia coli Downregulate DNA Mismatch Repair Protein In Vitro and Are Associated with Colorectal Adenocarcinomas in Humans

Abstract

BackgroundMucosa-associated Escherichia coli are frequently found in the colonic mucosa of patients with colorectal adenocarcinoma, but rarely in healthy controls. Chronic mucosal E. coli infection has therefore been linked to colonic tumourigenesis. E. coli strains carrying eae (encoding the bacterial adhesion protein intimin) attach intimately to the intestinal mucosa and are classed as attaching and effacing E. coli (AEEC). Enteropathogenic Escherichia coli (EPEC) are the most common form of AEEC identified in man. EPEC utilise a type III secretion system to translocate effector proteins into host cells and infection induces wide-ranging effects on the host cell proteome. We hypothesised that EPEC infection could influence molecular pathways involved in colorectal tumourigenesis.Methodology/Principal FindingsWhen co-cultured with human colorectal cell lines, EPEC dramatically downregulated the expression of key DNA mismatch repair proteins MSH2 and MLH1 in an attachment specific manner. Cytochrome c staining and TUNEL analysis confirmed that this effect was not a consequence of apoptosis/necrosis. Ex vivo human colonic mucosa was co-cultured with EPEC and probed by immunofluorescence to locate adherent bacteria. EPEC entered 10% of colonic crypts and adhered to crypt epithelial cells, often in the proliferative compartment. Adenocarcinoma and normal colonic mucosa from colorectal cancer patients (n = 20) was probed by immunofluorescence and PCR for AEEC. Mucosa-associated E. coli were found on 10/20 (50%) adenocarcinomas and 3/20 (15%) normal mucosa samples (P<0.05). AEEC were detected on 5/20 (25%) adenocarcinomas, but not normal mucosa samples (P<0.05).Significance/ConclusionsThe ability of EPEC to downregulate DNA mismatch repair proteins represents a novel gene-environment interaction that could increase the susceptibility of colonic epithelial cells to mutations and therefore promote colonic tumourigenesis. The potential role of AEEC in colorectal tumourigenesis warrants further investigation.

Screening for Host Proteins Interacting with Escherichia Coli O157:H7 EspF using Bimolecular Fluorescence Complementation

“…A cohort study showed that E. coli adherence to colonic mucosa may be linked to colorectal cancer [85]. Moreover, EPEC infection can activate PKCα, phosphorylate Bcl-2 and inhibit the transcription of MMR genes [86]. A/E E. coli infected intestinal epithelial cells by injecting toxic proteins, leading to DNA damage in host cells, and, together with the Toll-like receptor signaling pathway, the NF-κB pathway and other cell inflammatory pathways, accelerated the process of cancer [86][87][88].…”

S100A8 facilitates the migration of colorectal cancer cells through regulating macrophages in the inflammatory microenvironment

“…Several studies have reported that CRC cells may be exposed to increased levels of LPS because of bacterial translocation (38) or systemic endogenous LPS without infections (39). It is suggested that LPS is an important component in the inflammatory microenvironment.…”

Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression

“…Acquisition of protumoral function by macrophages is directly influenced by tumor microenvironment. As several independent studies have reported high colonization by E. coli of adenomas and carcinomas in colon cancer patients, [15][16][17][18][19] we have analyzed the effect of such a microbial environmental factor on COX-2 expression in human macrophages. Phagocytic uptake of pathogens by macrophages results in the formation of vacuoles that rapidly evolve into bactericidal Figure 3 Intramacrophagic persistence of E. coli strains isolated from colon cancer patients.…”

“…[10][11][12][13][14] In addition, our group and others have shown that colonic adenomas, carcinomas, and the mucosa of CRC patients are abnormally colonized by Escherichia coli belonging to the B2 phylogroup, with a high prevalence of E. coli producing a genotoxin, termed colibactin, encoded by the pks genomic island. [15][16][17][18][19][20] It has been recently demonstrated that cells that survive infection with colibactin-producing E. coli display hallmarks of cellular senescence accompanied with production of reactive oxygen species and secretion of pro-inflammatory cytokines, chemokines, and proteases, inducing bystander genotoxic and oncogenic effects. 21,22 Macrophages are one of the predominant components of murine and human tumor-infiltrating cells.…”