We have shown that human colon adenomas and carcinomas show a profound deficiency of retinoic acid biosynthetic enzymes and that APC controls intestinal cell differentiation by controlling the expression of retinol dehydrogenases. These findings suggest a novel model wherein APC promotes enterocyte differentiation by controlling retinoic acid biosynthesis and indicates that the functions of APC are not limited to its well-established role in regulating canonical WNT signaling. Mechanistically, we have identified the transcriptional co-repressor, C-terminal binding protein (CtBP), as a novel, APC-regulated protein that suppresses retinol dehydrogenases and intestinal cell differentiation. Consistent with APC control of CtBP, human adenomas taken from FAP patients showed robust staining for nuclear CtBP in comparison to adjacent, uninvolved tissues. Surprisingly, however, these same sections showed little evidence of nuclear B-catenin suggesting that accumulation of CtBP may precede nuclear accumulation of B-catenin and that nuclear accumulation of B-catenin may require events in addition to loss of APC. Consistent with this possibility are a number of reports showing that activation of (B-catenin signaling in small versus large adenomas appears to parallel activating mutations in the k-ras oncogene. Further, work in mice carrying a mutation typical of those found in human FAP has shown that activation of k-ras increased polyp size and number. These data suggest that k-ras activation permits B-catenin-stimulated intestinal cell proliferation during the formation of a large adenoma. Indeed our preliminary data show that APC loss alone is insufficient to promote intestinal cell proliferation in zebrafish. Furthermore, oncogenic k-ras promotes the accumulation of nuclear B-catenin and subsequent proliferation in both human cells and zebrafish. Our access to both FAP and undefined high-risk families, as well as our expertise in using zebrafish as a genetic model system to study APC, provides us a unique opportunity to evaluate the contribution of CtBP and k-ras in the initiation and progression of colon adenomas.

Public Health Relevance

Our long-term goal is to facilitate the development of new preventive measures for colon adenoma formation by understanding the earliest cellular perturbations that follow APC mutation. This project supports our long-term goal in a number of ways. First, it will expand our understanding of how APC contributes to the development of normal intestinal epithelium. This understanding could support a testable clinical hypothesis using new combined therapies for preventing human colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA073992-14
Application #
8449514
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
2013-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
14
Fiscal Year
2013
Total Cost
$276,677
Indirect Cost
$83,478
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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