Escherichia coli and Colorectal Carcinogenesis

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DESCRIPTION (provided by applicant): Cancers of the large intestine cause more deaths in the United States than those arising in any other organ but the lung. Despite tremendous progress, the factors that initiate and promote the progression of neoplasia in the colon are incompletely understood. Our preliminary data suggest that Escherichia coli and in particular E. coli strains that have the E. coli attaching and effacing (eae) gene are associated with colon carcinoma in humans. Furthermore, we have found that attaching and effacing E. coli (AEEC) strains specifically down-regulate expression of mismatch repair (MMR) proteins MLH1 and MSH2. These proteins protect against mutations during DNA replication and patients with certain inherited and some with sporadic colorectal cancer have mutations in these genes. Our preliminary microarray data also indicate that AEEC down-regulate DKK1, an inhibitor of the Wnt pathway, which plays an important role in cell proliferation and is inappropriately activated in another inherited form of colorectal cancer. AEEC also down-regulate several critical components of the innate immune response. Together, these data provide tantalizing evidence to suggest the following novel hypothesis: AEEC play a role in colonic carcinogenesis through T3SS-dependent inhibition of host cell processes that defend against microbial colonization, DNA damage and unregulated cell growth. The goal of this proposal is to gather additional data to determine whether this hypothesis is tenable. We plan to determine whether specific AEEC proteins are required to down-regulate MMR protein expression and whether we can detect decreased MMR activity in infected human colon carcinoma cell lines and evidence of increased genomic instability in infected human neoplastic tissue. We plan to determine whether we can verify the microarray data regarding inhibition of DKK1 and activators of the innate immune response at the mRNA and protein level. We also plan to accrue a collection of normal and neoplastic human colonic tissue with which we can attempt to verify and further characterize the association between AEEC and colonic neoplasia. The results of these studies will indicate whether further research is justified to determine the role of AEEC in colorectal carcinogenesis. Ultimately this work could have profound implications for the diagnosis, prevention and treatment of a one of the leading causes of cancer mortality. PUBLIC HEALTH RELEVANCE: Cancers arising in the large intestine kill more Americans than those from any other organ but the lung. Despite tremendous progress in deciphering the genetic changes that lead to these cancers, there is much to learn about how the process begins. We have found that certain types of E. coli bacteria are found attached to cancers of the large intestine and that these same bacteria can interfere with the ability of intestinal cells to repair mistakes in DNA. These same mistakes are important in the development of cancer. We wish to explore further the ability of these bacteria to interfere with this and other pathways that protect against cancer to determine whether certain strains of bacteria may play a role in cancer development.