Colorectal Cancer Prevention Through Thyroid Hormone Targets

Summary

Principal Investigator: ADAM ROBERT BROWN
Abstract: DESCRIPTION (provided by applicant): 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[unreadable]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[unreadable]1 expression. RNA and protein will be extracted from adenomas and uninvolved mucosa and expression levels of KLF9, TR[unreadable]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.
Funding Period: 2012-03-01 - 2015-02-28
more information: NIH RePORT

Top Publications

  1. pmc The role of thyroid hormone signaling in the prevention of digestive system cancers
    Adam R Brown
    Interdisciplinary Biomedical Sciences Program, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
    Int J Mol Sci 14:16240-57. 2013

Research Grants

  1. Dietary Factors in Colon Cancer Prevention
    FRANK ALBERT SIMMEN; Fiscal Year: 2013
  2. Mechanisms of CDX2 regulation of the IGF axis
    Duyen Dang; Fiscal Year: 2013
  3. MODULATION OF INTESTINAL HOMEOSTASIS AND CANCER
    Leonard H Augenlicht; Fiscal Year: 2013
  4. Dietary Risk for Colon Cancer in the Mouse
    Leonard H Augenlicht; Fiscal Year: 2013

Detail Information

Publications1

  1. pmc The role of thyroid hormone signaling in the prevention of digestive system cancers
    Adam R Brown
    Interdisciplinary Biomedical Sciences Program, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
    Int J Mol Sci 14:16240-57. 2013
    ....

Research Grants30

  1. Dietary Factors in Colon Cancer Prevention
    FRANK ALBERT SIMMEN; Fiscal Year: 2013
    ..These studies have strong translational significance for improving the health and quality of life of the overweight/obese population at risk for or afflicted with colo-rectal cancer. ..
  2. Mechanisms of CDX2 regulation of the IGF axis
    Duyen Dang; Fiscal Year: 2013
    ..This line of investigation provides the first insights into how CDX2 can function as both a cell growth promoter and suppressor. This approach would hopefully lead to novel clinical strategies for colon cancer prevention and therapy. ..
  3. MODULATION OF INTESTINAL HOMEOSTASIS AND CANCER
    Leonard H Augenlicht; Fiscal Year: 2013
    ..abstract_text> ..
  4. Dietary Risk for Colon Cancer in the Mouse
    Leonard H Augenlicht; Fiscal Year: 2013
    ..abstract_text> ..