Previous studies have suggested that expression of the three-zinc-finger transcription factor Krüppel-Like Factor 9 (KLF9) is down-regulated in both colorectal cancer (CRC) and hepatocellular carcinoma (HCC) in contrast to surrounding healthy tissue, suggesting a tumor-suppressive role in each tissue type. Additionally, KLF9 has been shown to facilitate adipocyte differentiation in vitro, suggesting that KLF9 may play a major role in development of obesity, a major risk factor for CRC and HCC. However, the in vivo role of KLF9 loss in CRC development, adipogenesis, and HCC risk has not been investigated. In chapter 2 of this dissertation, I examined the effects of absence of KLF9 on intestinal tumorigenesis in the Apc Min/+ mouse, a genetic model of intestinal cancer. Both ApcMin/+/Klf9+/- and Apc Min/+/Klf9-/- mice exhibited increased numbers of colon adenomas, but not adenomas of the small intestine, relative to ApcMin/+/Klf9+/+ mice of both sexes. Full and partial loss of Klf9 in ApcMin/+ mouse colon mucosa was accompanied by increased mRNA expression of a number of interferon-stimulated genes. Similar results were seen with siRNA knockdown of KLF9 in HT29 human CRC cells. Of note, ISG15 was significantly increased with KLF9 loss in ApcMin/+ mice and HT29 cells, and ISG15 was shown to inhibit apoptosis in HT29 cells; thus providing a novel mechanistic link between KLF9 and suppression of CRC. To examine if KLF9 loss impacts development of obesity and related parameters as a risk factor for CRC, Klf9+/+ and Klf9-/- mice were place on a high fat diet (HFD) for 12 weeks and examined for weight gain and obesity-related indices. Loss of Klf9 did not significantly alter adiposity, hepatosteatosis, or serum leptin/adiponectin levels. However, Klf9-/- mice did exhibit increased levels of markers for oxidative and nitrosative stress in the liver and serum. These results suggest a role for KLF9 in reducing hepatic oxidative stress, which may be a protective mechanism in the prevention of HCC. Increased systemic oxidative stress, driven in part by hepatic oxidative stress may impact pathogenesis in other organ systems, including the colon. Cumulatively, these results suggest direct and indirect protective effects of KLF9 in colon and liver pathogenesis. Hormonal or pharmaceutical induction of KLF9 may therefore provide a means of prevention and/or treatment of CRC and HCC.
|Advisor:||Simmen, Frank A.|
|Commitee:||Haun, Randy S., MacLeod, Stewart L., Simmen, Rosalia C.M., Ware, Jerry|
|School:||University of Arkansas for Medical Sciences|
|Department:||Interdisciplinary Biomedical Sciences|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 76/09(E), Dissertation Abstracts International|
|Keywords:||Colorectal cancer, Hepatocellular carcinoma, Obesity|
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