Regulation of cyclooxygenase-2 by ErbB4 in colon epithelial cells

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DESCRIPTION (provided by applicant): Inflammatory bowel diseases are associated with an increased risk of early-onset colorectal cancer, resulting in great cost both economically and in patient morbidity and mortality. Intensive research has been focused on identifying signaling pathways active in both inflammation and cancer, which may thus be targets of therapy or chemoprevention. The ErbB4 tyrosine kinase, a member of the epidermal growth factor-related ErbB growth factor receptor family, is expressed at elevated levels in colitis and in a subset of human colorectal cancers. This receptor is thus a candidate participant in colitis-associated tumorigenesis. We recently demonstrated that ErbB4 expression and activity are induced by tumor necrosis factor, and that ErbB4 in turn promotes colon epithelial cell survival in the presence of pro-inflammatory cytokines. Preliminary data developed for this application further show that ErbB4 promotes colon epithelial cell transformation in both in vitro and in vivo models. Furthermore, ErbB4-induced cell survival and transformation are associated with increased mRNA stability and protein levels for the prostaglandin synthase cyclooxygenase-2 (COX-2). Thus, this application proposes to test the hypothesis that ErbB4 promotes colon epithelial cell survival and transformation in the inflammatory milieu through a COX-2-dependent mechanism. Planned experiments will use coordinated in vitro (signal transduction analysis, apoptosis & and colony formation assays) and in vivo (nude mouse xenograft tumor formation assays) approaches to (1) Identify signaling pathways involved in ErbB4-induced COX-2 expression, and (2) investigate cooperation between ErbB4 and COX-2 in colon epithelial cell survival and transformation.