Colorectal cancer is the third most prevalent type of cancer and ranks second as the major cause of cancer-related deaths in the US population. The median age of diagnosis for colorectal cancer is 71, demonstrating that it is primarily a disease of old age. Studies have suggested that thyroid hormone may have a role in colon cancer prevention. Other studies have shown that many elderly patients exhibit sub-clinical hypothyroidism and decreased thyroid hormone sensitivity. Kr?ppel-like factor 9 (KLF9) is a thyroid hormone- induced transcription factor, and a putative tumor suppressor of the human colo-rectum. The goal of this proposal is to investigate a proposed mechanism by which KLF9 prevents colorectal tumorigenesis in mice, and to evaluate the effects of aging on this relationship. My preliminary data suggest that KLF9 is a negative regulator of fatty acid synthase (FASN) in vitro, which is a gene commonly up-regulated in colon adenocarcinomas, and a potential therapeutic target for cancer. This application proposes two aims to test the hypothesis that aging, via acute reduction in circulating thyroid hormone and decreased thyroid hormone sensitivity, results in a reduction in colon mucosal expression of KLF9, which leads to increased expression of FASN. Further, we propose that KLF9 functions as a tumor suppressor of the colon, and that loss of Klf9 alleles will increase number and size of intestinal tumors in ApcMin/+ mice.
Aim 1 seeks to determine if aging will, via decreased thyroid hormone sensitivity, decrease colonic expression of Klf9 and thereby increase colonic expression of Fasn in aged mice. Colons of mice at ages 6, 12, and 18 months will be collected and mucosal expression levels of Klf9 and Fasn will be evaluated at the mRNA and protein levels.
Aim 2 will determine whether colonic expression of Klf9 affects intestinal tumorigenesis by crossing Klf9 knockout mice with ApcMin/+ mice and measuring tumor incidence and development. Small and large intestines will be removed from ApcMin/+ mice with two, one, or no Klf9 alleles and tumor number and sizes will be recorded. The largest adenomas will be subjected to immunohistochemistry to monitor phosphohistone H3, TUNEL, KLF9, and Tr?1 expression. RNA and protein will be extracted from adenomas and uninvolved mucosa and expression levels of KLF9, TR?1, FASN, and telomerase reverse transcriptase (TERT) will be evaluated by Western blot and qPCR. Finally, micro-adenomas will be quantified by H&E staining and counting. The successful completion of the study will provide insight into potential age-dependent targets that may lead to the development of new therapies to prevent or treat age-related colorectal cancer.

Public Health Relevance

Colorectal cancer is the second greatest cause of cancer-related death in Western countries, and is most commonplace in elderly patients. Although a number of different causes for colorectal cancer exist, there remains an evident and persistent need to identify the physiological and molecular mechanisms responsible for the high incidence of this disease in the aging population. The proposed animal studies are aimed at understanding the role of age- related hormonal changes in the development of colorectal cancer, as well as to evaluate a potential mechanism behind this change. The findings of these studies may lead to the implementation of new therapies to prevent or treat colorectal cancer in the burgeoning elderly population.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F09-D (20))
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Schmidt, Michael K
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University of Arkansas for Medical Sciences
Schools of Medicine
Little Rock
United States
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Brown, Adam R; Simmen, Rosalia C M; Raj, Vinay R et al. (2015) Kr├╝ppel-like factor 9 (KLF9) prevents colorectal cancer through inhibition of interferon-related signaling. Carcinogenesis 36:946-55
Al-Dwairi, Ahmed; Brown, Adam R; Pabona, John Mark P et al. (2014) Enhanced gastrointestinal expression of cytosolic malic enzyme (ME1) induces intestinal and liver lipogenic gene expression and intestinal cell proliferation in mice. PLoS One 9:e113058
Brown, Adam R; Simmen, Rosalia C M; Simmen, Frank A (2013) The role of thyroid hormone signaling in the prevention of digestive system cancers. Int J Mol Sci 14:16240-57