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

@article{10.1371/journal.pone.0005517, abstract = {<sec> <title>Background</title> <p>Mucosa-associated <italic>Escherichia coli</italic> are frequently found in the colonic mucosa of patients with colorectal adenocarcinoma, but rarely in healthy controls. Chronic mucosal <italic>E. coli</italic> infection has therefore been linked to colonic tumourigenesis. <italic>E. coli</italic> strains carrying <italic>eae</italic> (encoding the bacterial adhesion protein intimin) attach intimately to the intestinal mucosa and are classed as attaching and effacing <italic>E. coli</italic> (AEEC). Enteropathogenic <italic>Escherichia coli</italic> (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.</p> </sec><sec> <title>Methodology/Principal Findings</title> <p>When 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 <italic>c</italic> staining and TUNEL analysis confirmed that this effect was not a consequence of apoptosis/necrosis. <italic>Ex vivo</italic> 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 <italic>E. coli</italic> 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).</p> </sec><sec> <title>Significance/Conclusions</title> <p>The 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.</p> </sec>}, author = {Maddocks, Oliver D. K. and Short, Abigail J. and Donnenberg, Michael S. and Bader, Scott and Harrison, David J.}, citeulike-article-id = {4533612}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pone.0005517}, citeulike-linkout-1 = {http://dx.doi.org/10.1371%2Fjournal.pone.0005517}, doi = {10.1371/journal.pone.0005517}, journal = {PLoS ONE}, keywords = {attachment, bacteria, cancer, coli, colon, dna, escherichia, repair}, number = {5}, posted-at = {2009-05-18 00:19:10}, priority = {2}, publisher = {Public Library of Science}, title = {Attaching and Effacing Escherichia coli Downregulate DNA Mismatch Repair Protein In Vitro and Are Associated with Colorectal Adenocarcinomas in Humans}, url = {http://dx.doi.org/10.1371/journal.pone.0005517}, volume = {4}, year = {2009} }

TY - JOUR ID - 10.1371/journal.pone.0005517 L3 - citeulike-article-id:4533612 N2 - <sec> <title>Background</title> <p>Mucosa-associated <italic>Escherichia coli</italic> are frequently found in the colonic mucosa of patients with colorectal adenocarcinoma, but rarely in healthy controls. Chronic mucosal <italic>E. coli</italic> infection has therefore been linked to colonic tumourigenesis. <italic>E. coli</italic> strains carrying <italic>eae</italic> (encoding the bacterial adhesion protein intimin) attach intimately to the intestinal mucosa and are classed as attaching and effacing <italic>E. coli</italic> (AEEC). Enteropathogenic <italic>Escherichia coli</italic> (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.</p> </sec><sec> <title>Methodology/Principal Findings</title> <p>When 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 <italic>c</italic> staining and TUNEL analysis confirmed that this effect was not a consequence of apoptosis/necrosis. <italic>Ex vivo</italic> 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 <italic>E. coli</italic> 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).</p> </sec><sec> <title>Significance/Conclusions</title> <p>The 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.</p> </sec> IS - 5 JF - PLoS ONE TI - Attaching and Effacing Escherichia coli Downregulate DNA Mismatch Repair Protein In Vitro and Are Associated with Colorectal Adenocarcinomas in Humans PB - Public Library of Science VL - 4 KW - attachment KW - bacteria KW - cancer KW - coli KW - colon KW - dna KW - escherichia KW - repair AU - Maddocks, Oliver AU - Short, Abigail AU - Donnenberg, Michael AU - Bader, Scott AU - Harrison, David PY - 2009/// UR - http://dx.doi.org/10.1371/journal.pone.0005517 ER -