Inflammatory bowel diseases are associated with increased risk of early-onset colorectal cancer, incurring great cost both economically and in patient morbidity and mortality. Intensive research has been focused on identifying signaling pathways which may be targets of therapy or chemoprevention in high-risk groups. One candidate molecule is ErbB-4, the most recently described member of the EGFR-related ErbB family of tyrosine kinase growth factor receptors. ErbB-4 is expressed in mammalian tissues as up to four distinct full length isoforms and two intercellular domain cleavage products, and is likely to participate in regulatory mechanisms distinct from those of other ErbB family members. Recent reports have shown ErbB-4 expression in colorectal carcinomas and a possible association with more aggressive disease, though the mechanisms underlying these data are unknown. Our preliminary results indicate that (1) ErbB-4 expression is increased in the intestinal epithelium during inflammation, (2) the proinflammatory cytokine TNF-? promotes ErbB-4 expression and activation in cultured mouse colon epithelial (MCE) cells, and (3) cell survival in the presence of pathologic TNF-? levels requires ErbB-4. Therefore we have developed the hypothesis that ErbB-4 isoforms promote chronic inflammation-induced colon carcinogenesis through increased cell survival, proliferation, and/or migration in the inflammatory environment. Proposed experiments will address this hypothesis through the following specific Aims: (1) Determine the requirement for ErbB-4 in inflammation-induced colon cancer by characterizing expression of ErbB-4 isoforms during tumorigenesis and determining the effect of ErbB-4 deletion on AOM/DSS tumorigenesis in vivo; (2) Define the role(s) of full-length and intracellular domain ErbB-4 isoforms in intestinal cell transformation by expressing individual ErbB-4 forms in ErbB-4-/- MCE cells and using these cells for in vitro transformation assays; and (3) Test the effect of ErbB-4 isoforms on intestinal tumor formation in vivo using an allograft tumor formation model. Overall, these studies are expected to clarify the role of ErbB-4 in colitis-associated carcinogenesis. They will also provide much-needed information on the relative roles of the different ErbB-4 isoforms in tissues that express multiple forms, and will potentially identify novel avenues of therapy and chemoprevention based on the activity these isoforms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01DK077956-06
Application #
8195441
Study Section
Special Emphasis Panel (ZDK1-GRB-R (J3))
Program Officer
Podskalny, Judith M,
Project Start
2007-04-01
Project End
2012-03-31
Budget Start
2011-04-01
Budget End
2012-03-31
Support Year
6
Fiscal Year
2011
Total Cost
$127,602
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
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Hobbs, Stuart S; Goettel, Jeremy A; Liang, Dongchun et al. (2011) TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 301:G220-9
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