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Impact of Epa and Dha Supplementation and 15-Lox-1 Expression on Colitis and Colitis-Associated Colorectal Cancer

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Impact of Epa and Dha Supplementation and 15-Lox-1 Expression on Colitis and Colitis-Associated Colorectal Cancer The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 5-2020 IMPACT OF EPA AND DHA SUPPLEMENTATION AND 15-LOX-1 EXPRESSION ON COLITIS AND COLITIS-ASSOCIATED COLORECTAL CANCER Jonathan Jaoude Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Biology Commons, Cancer Biology Commons, Immunopathology Commons, and the Lipids Commons Recommended Citation Jaoude, Jonathan, "IMPACT OF EPA AND DHA SUPPLEMENTATION AND 15-LOX-1 EXPRESSION ON COLITIS AND COLITIS-ASSOCIATED COLORECTAL CANCER" (2020). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 1008. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1008 This Thesis (MS) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. IMPACT OF EPA AND DHA SUPPLEMENTATION AND 15-LOX-1 EXPRESSION ON COLITIS AND COLITIS-ASSOCIATED COLORECTAL CANCER by Jonathan Jaoude, B.S., M.A. APPROVED: ______________________________ Imad Shureiqi, M.D., M.S. Advisory Professor ______________________________ Peiying Yang, M.S., Ph.D. ______________________________ David Volk, Ph.D. ______________________________ Donghui Li, Ph.D ______________________________ Kimberly Schluns, Ph.D. APPROVED: ____________________________ Dean, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences IMPACT OF EPA AND DHA SUPPLEMENTATION AND 15-LOX-1 EXPRESSION ON COLITIS AND COLITIS-ASSOCIATED COLORECTAL CANCER A THESIS Presented to the Faculty of The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE by Jonathan Jaoude, B.S., M.A. Houston, Texas May 2020 IMPACT OF EPA AND DHA SUPPLEMENTATION AND 15-LOX-1 EXPRESSION ON COLITIS AND COLITIS-ASSOCIATED COLORECTAL CANCER Jonathan Jaoude, B.S., M.A. Advisory Professor: Imad Shureiqi, M.D., M.S. ABSTRACT: Inflammatory bowel disease (IBD) patients not only suffer from colitis but also from increased morbidity and mortality of colitis-associated colorectal cancer (CAC). The enzyme 15-lipoxygenase-1 (15-LOX-1) is crucial to converting omega-3 fatty acid derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to resolvins, potent anti- inflammatory products. 15-LOX-1 effects on the conversion of EPA and DHA to resolvins that subsequently exert anti-inflammatory and anti-tumorigenic effects have received little attention. To address this knowledge gap, we hypothesize that 15-LOX-1 expression in colonic epithelial cells is essential for resolvin biosynthesis from EPA and DHA to modulate immunophenotype, limit inflammation, promote resolution, and help prevent colitis and CAC. Mice were treated with dextran sodium sulfate (DSS) alone only to induce acute and chronic colitis, or with DSS following an azoxymethane injection to induce CAC. In the chronic colitis model, DHA diet and/or expression of 15-LOX-1 reduced inflammation and altered immune cell populations. In the CAC model, DHA reduces tumor numbers by 54% in the WT/DHA group and by 52% in the 15-LOX-1/DHA group. Increased levels of 17-HDHA, RvD1, RvD4, and RvD5 in the 15- LOX-1/DHA group were inversely correlated to tumor number. EPA diet with and without expression of 15-LOX-1 reduced tumors by 47-48%. In conclusion, our study strongly supports the critical role of 15-LOX-1 for RvD production from DHA. CAC suppression occurred with DHA supplementation with and without 15-LOX-1 transgenic expression and seems to be less dependent on the production of RvDs. Further in-depth mechanistic studies are therefore needed to be better define the role of resolvins in CAC and colonic tumorigenesis in general. iii Table of Contents Approval Sheet................................................................................................................................ i Title Page ....................................................................................................................................... ii Abstract ......................................................................................................................................... iii Table of Contents .......................................................................................................................... iv List of Illustrations ......................................................................................................................... v List of Tables ................................................................................................................................. v Abbreviations ................................................................................................................................. v Introduction ................................................................................................................................. 1-3 Materials and Methods .............................................................................................................. 3-13 Results ..................................................................................................................................... 13-25 Characterization of the Novel Rosa-i15-LOX-1 Mouse Model ................................. 13-14 Effects of 15-LOX-1 and DHA on Acute and Chronic Colitis ................................... 14-15 Effects of 15-LOX-1 and DHA on Immune Cells ..................................................... 15-19 Effects of 15-LOX-1 and DHA on CAC ................................................................... 19-21 Effects of 15-LOX-1 and DHA on Resolvin Production ........................................... 21-22 Effects of 15-LOX-1 and DHA on Eicosanoid Products ........................................... 22-23 Effects of 15-LOX-1 and EPA on CAC ..................................................................... 23-25 Discussion ............................................................................................................................... 26-30 Bibliography ........................................................................................................................... 31-44 Vita ............................................................................................................................................... 45 iv List of Illustrations Figure 1. Strategy for generating a new inducible 15-LOX-1 mouse model (i15-LOX-1). Page 4. Figure 2. Effects of dextran sulfate sodium (DSS) induced colitis on body weight. Page 6. Figure 3. Characterization of the new Rosa-i15-LOX-1 mouse model. Page 14. Figure 4. Effects of 15-LOX-1 modulation of docosahexaenoic acid (DHA) on dextran sulfate sodium (DSS) induced colitis. Page 14. Figure 5. Immune profile of DSS-induced acute colitis. Page 17. Figure 6. Immune profile of DSS induced chronic colitis. Page 18. Figure 7. Effects of 15-LOX-1 modulation of docosahexaenoic acid (DHA) on dextran sulfate sodium (DSS)/azoxymethane (AOM)-induced colonic tumorigenesis. Page 20. Figure 8. Effects of 15-LOX-1 modulation of resolvins on dextran sulfate sodium (DSS)/azoxymethane (AOM)-induced colonic tumorigenesis. Page 21. Figure 9. Effects of 15-LOX-1 modulation of eicosanoid products on dextran sulfate sodium (DSS)/azoxymethane (AOM)-induced colonic tumorigenesis. Page 23. Figure 10. Effects of 15-LOX-1 modulation of eicosapentaenoic acid (EPA) on dextran sulfate sodium (DSS)/azoxymethane (AOM)-induced colonic tumorigenesis. Page 24. List of Tables Table 1. Immunophenotyping of mouse immune subsets by flow cytometry. Pages 15-16. Abbreviations: colorectal cancer (CRC), colitis-associated colorectal cancer (CAC), inflammatory bowel disease (IBD), polyunsaturated fatty acid (PUFA), azoxymethane (AOM), dextran sodium sulfate (DSS), docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), E/D- series resolvins (RvE/D), 15-lipoxygenase-1 (15-LOX-1). v 1. Introduction Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer death in the world (1). Inflammatory bowel disease (IBD) patients not only suffer from colitis but also from increased morbidity and mortality for colitis-associated colorectal cancer (CAC). A global meta-analysis measured a 0.3% incidence rate per year for CAC (2), and a CRC prevalence of 3.7% with colitis patients (3). Though the incidence rate and prevalence of CAC seem low, IBD is the third highest risk factor for developing CRC. An estimated 10-15% of deaths in IBD patients are related to colorectal cancer (4). Evidently, it is important to treat IBD as a preventative measure to reduce CAC. Fish oil and its omega-3 polyunsaturated fatty acid (PUFA) derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are widely promoted as agents that prevent chronic inflammation and cancer.
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