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 #
5P01CA073992-15
Application #
8627124
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$261,824
Indirect Cost
$77,832
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Burt, Randall W (2016) Screening and Survival in Familial Adenomatous Polyposis. J Clin Gastroenterol 50:3-4
Samadder, N Jewel; Curtin, Karen; Pappas, Lisa et al. (2016) Risk of Incident Colorectal Cancer and Death After Colonoscopy: A Population-based Study in Utah. Clin Gastroenterol Hepatol 14:279-86.e1-2
Samadder, N Jewel; Smith, Ken Robert; Hanson, Heidi et al. (2016) Familial Risk in Patients With Carcinoma of Unknown Primary. JAMA Oncol 2:340-6
Li, Jun; Woods, Susan L; Healey, Sue et al. (2016) Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant. Am J Hum Genet 98:830-42
Samadder, N Jewel; Neklason, Deborah W; Boucher, Kenneth M et al. (2016) Effect of Sulindac and Erlotinib vs Placebo on Duodenal Neoplasia in Familial Adenomatous Polyposis: A Randomized Clinical Trial. JAMA 315:1266-75
Samadder, N J; Smith, K R; Mineau, G P et al. (2015) Familial colorectal cancer risk by subsite of primary cancer: a population-based study in Utah. Aliment Pharmacol Ther 41:573-80
Gammon, Amanda; Neklason, Deborah W (2015) Confidentiality & the Risk of Genetic Discrimination: What Surgeons Need to Know. Surg Oncol Clin N Am 24:667-81
Samadi, Abbas K; Bilsland, Alan; Georgakilas, Alexandros G et al. (2015) A multi-targeted approach to suppress tumor-promoting inflammation. Semin Cancer Biol 35 Suppl:S151-84
Samadder, N Jewel; Smith, Ken Robert; Hanson, Heidi et al. (2015) Increased Risk of Colorectal Cancer Among Family Members of All Ages, Regardless of Age of Index Case at Diagnosis. Clin Gastroenterol Hepatol 13:2305-11.e1-2

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