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.

Public Health Relevance

Patients with inflammatory bowel diseases are at elevated risk for the development of colorectal cancer, but the exact molecular mechanisms underlying this increased risk are poorly understood. The proposed studies will advance our mechanistic understanding of cellular signaling in inflammation and carcinogenesis, with implications for the development of novel clinical therapies targeting ErbB4 and COX-2.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK090295-01
Application #
8031551
Study Section
Special Emphasis Panel (ZDK1-GRB-7 (O3))
Program Officer
Podskalny, Judith M,
Project Start
2011-04-01
Project End
2013-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
1
Fiscal Year
2011
Total Cost
$80,000
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Bower, Danielle V; Lansdale, Nick; Navarro, Sonia et al. (2017) SERCA directs cell migration and branching across species and germ layers. Biol Open 6:1458-1471
Williams, Christopher S; Bernard, Jessica K; Demory Beckler, Michelle et al. (2015) ERBB4 is over-expressed in human colon cancer and enhances cellular transformation. Carcinogenesis 36:710-8
McElroy, Steven J; Castle, Shannon L; Bernard, Jessica K et al. (2014) The ErbB4 ligand neuregulin-4 protects against experimental necrotizing enterocolitis. Am J Pathol 184:2768-78
Frey, Mark R; Brent Polk, D (2014) ErbB receptors and their growth factor ligands in pediatric intestinal inflammation. Pediatr Res 75:127-32
Williams, Jonathan M; Duckworth, Carrie A; Watson, Alastair J M et al. (2013) A mouse model of pathological small intestinal epithelial cell apoptosis and shedding induced by systemic administration of lipopolysaccharide. Dis Model Mech 6:1388-99
Bernard, Jessica K; McCann, Sean P; Bhardwaj, Vrinda et al. (2012) Neuregulin-4 is a survival factor for colon epithelial cells both in culture and in vivo. J Biol Chem 287:39850-8
Al Alam, Denise; Sala, Frederic G; Baptista, Sheryl et al. (2012) FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. Dev Biol 369:340-8
Rosen, Michael J; Frey, Mark R; Washington, M Kay et al. (2011) STAT6 activation in ulcerative colitis: a new target for prevention of IL-13-induced colon epithelial cell dysfunction. Inflamm Bowel Dis 17:2224-34
Frey, Mark R; Hilliard, Valda C; Mullane, Matthew T et al. (2010) ErbB4 promotes cyclooxygenase-2 expression and cell survival in colon epithelial cells. Lab Invest 90:1415-24