Colorectal neoplasia is a leading cause of cancer morbidity and mortality in the United States. Although the genomics revolution has resulted in high profile advances in cancer therapeutics, these have not translated into a definitive improvement in the survival of patients with advanced disease. Thus, it is critical to continue the study of the molecular pathogenesis of colon cancer with the goal of improved diagnosis and treatment. Over the past decade, we have studied the autocrine growth inhibitory factor, transforming growth factor beta(TGFbeta), in normal and aberrant intestinal epithelial growth. During this interval, TGFbet, its receptor, and the Smad signaling pathway have been decisively recognized as a critical axis of tumor suppression in the intestinal epithelium. In certain contexts however, TGFbeta signaling may contribute to tumor promotion, a duality of function that is increasingly recognized in neoplastic disorders. We propose to explore this dual activity of TGFbeta in in vivo and in vitro models of intestinal neoplasia, especially in the context of oncogenic Ras, which we have defined as a key repressor of growth inhibitory Smad-dependent TGFbeta signaling. The overarching hypothesis is that TGFbeta is a tumor suppressor via Smad-dependent signaling early in tumorigenesis. At later stages of disease TGFbeta signaling switches, in part under the influence of oncogenic Ras, to tumor promotion.
The specific aims are to 1) test the hypothesis that histone deacetylases are Smad-binding partners and modulators of Smad-dependent signaling; 2) test the hypothesis, using microarray analysis, that TGFbeta induces a unique transcriptome in Ras-transformed cells and then use the results to further characterize TGFbeta as a tumor promoter; 3) test the hypothesis that TGFbeta will have both tumor suppressing and tumor promoting functions in animal models of TGFbeta signaling and colorectal cancer using genetically engineered mice in which TGFbeta signaling is enhanced. Dissection of the pathways involved in the tumor suppressive versus the tumor promoting effects of TGFbeta will lead to opportunities to selectively inhibit its undesirable effects without compromising its tumor suppressive functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059656-06
Application #
7048616
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
May, Michael K
Project Start
2000-09-01
Project End
2010-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
6
Fiscal Year
2006
Total Cost
$305,059
Indirect Cost
Name
Nationwide Children's Hospital
Department
Type
DUNS #
147212963
City
Columbus
State
OH
Country
United States
Zip Code
43205
Matta, Ranyia; Barnard, John A; Wancket, Lyn M et al. (2012) Knockout of Mkp-1 exacerbates colitis in Il-10-deficient mice. Am J Physiol Gastrointest Liver Physiol 302:G1322-35
Yakovich, Adam J; Jiang, Bo; Allen, Carl E et al. (2011) ZAS3 accentuates transforming growth factor ? signaling in epithelial cells. Cell Signal 23:105-13
Barnard, John (2009) Screening and surveillance recommendations for pediatric gastrointestinal polyposis syndromes. J Pediatr Gastroenterol Nutr 48 Suppl 2:S75-8
Yang, Jing; Chan, Chin Yee; Jiang, Bo et al. (2009) hnRNP I inhibits Notch signaling and regulates intestinal epithelial homeostasis in the zebrafish. PLoS Genet 5:e1000363