attaching and effacing escherichia coli downregulate dna mismatch repair protein in vitro and are associated with colorectal adenocarcinomas in humans附加和消除大肠杆菌表达下调dna错配修复蛋白在体外,在人类与结直肠腺癌相关联.pdf

Attaching and Effacing Escherichia coli Downregulate DNA Mismatch Repair Protein In Vitro and Are Associated with Colorectal Adenocarcinomas in Humans 1,2 1 2 1 1 Oliver D. K. Maddocks *, Abigail J. Short , Michael S. Donnenberg , Scott Bader , David J. Harrison 1 Division of Pathology, Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom, 2 Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore, Maryland, United States of America Abstract Background: Mucosa-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 Findings: 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 c staining and TUNEL analysis confirmed that this effect was not a consequence of apoptosis/necrosis. Ex vivo human colonic mucosa