Inflammatory bowel disease (IBD), which affects 1 in 600 Americans, is characterized by severe and chronic inflammation, a known contributor to cancer. As such, the risk for cancer is increased in patients with IBD compared with the general population, and cancer is the most significant cause of mortality in IBD. This thesis will identify modifiers of colitis-associated cancer (CAC) utilizing a murine CAC model applied to models of dietary and genetic deficiencies.
First, this thesis will focus on dietary selenium and two plasma selenoproteins as suppressors of tumorigenesis. Selenium deficiency results in increased inflammation in response to an inflammatory model utilizing dextran sodium sulfate (DSS) which, when coupled with the use of an initiator, azoxymethane (AOM/DSS inflammatory carcinogenesis model), leads to an increase in tumorigenesis concomitant with an increase in DNA damage. Knockout of the plasma selenoprotein glutathione peroxidase-3 (Gpx3) also results in increased tumor number as well as a higher degree of dysplasia. Finally, I demonstrate that selenoprotein P (Sepp1), which is considered to have both selenium transport and antioxidant properties, is a bimodal modifier of CAC. Complete loss of Sepp1 leads to decreased tumorigenesis as the result of clearance of initiated cells while haploinsufficiency leads to an increase in tumorigenesis which is mimicked by loss of either the putative selenium transport or antioxidant domains of Sepp1.
A second set of CAC modifiers identified in this thesis are the myeloid translocation genes (MTGs). The MTGs are a family of transcriptional corepressors that were originally identified as targets of chromosomal translocations in acute myeloid leukemia. This thesis will first identify MTG, related-1 (MTGR1) as a modifier of inflammation which, upon its loss, leads to a decrease in inflammatory carcinogenesis. Moreover, I identify an interaction between MTG16 and the transcriptional repressor Kaiso. Knockout of MTG16 alone leads to increased tumorigenesis while knockout of Kaiso leads to unaltered tumorigenesis. Interestingly, absence of both proteins leads to rescue of the MTG16 phenotype, suggesting that Kaiso is epistatic to MTG16.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-09152013-171949 |
| Date | 23 September 2013 |
| Creators | Barrett, Caitlyn Whitten |
| Contributors | Raymond Burk, Scott Hiebert, Christopher Williams, Barbara Fingleton, Albert Reynolds |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-09152013-171949/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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