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Alterations in Endogenous Retinoids with Acute UVB Exposure and in the Progression of Cutaneous Squamous Cell Carcinoma

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Alterations in Endogenous Retinoids with Acute UVB Exposure and in the Progression of Cutaneous Squamous Cell Carcinoma Alterations in Endogenous Retinoids with Acute UVB Exposure and in the Progression of Cutaneous Squamous Cell Carcinoma THESIS Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Katherine Gressel Graduate Program in Human Nutrition The Ohio State University 2015 Master's Examination Committee: Dr. Helen Everts, Advisor Dr. Earl Harrison Dr. Tatiana Oberyszyn Copyrighted by Katherine Gressel 2015 Abstract Exposure to UVB light is the largest risk factor for the development of cutaneous squamous cell carcinoma (cSCC), one of the most common cancers in the United States. UVB exposure causes many changes to occur in the skin such as epidermal thickening, hyperproliferation, and alterations to epidermal differentiation. Retinoids regulate the differentiation and proliferation of the epidermis. The purpose of this study is to examine how the expression of retinoid metabolism proteins in the epidermis is altered with acute UVB exposure and in the progression of cSCC. There is limited knowledge of how UVB exposure may affect this pathway; our results will allow us to gain a more complete understanding of changes in the entire retinoid metabolism pathway. We examined the expression of key retinoic acid metabolism proteins in the epidermis and hair follicle remnants 48 hours after UVB exposure in SKH-1 mice using immunohistochemistry. UVB exposure increased the expression of retinoid synthesis, degradation, and binding proteins. These changes in expression suggest that acute UVB exposure increases the synthesis of retinoic acid in the epidermis. Many of these proteins changed their localization in the epidermis, concentrating in the more differentiated cells of the stratum granulosum and stratum corneum. To determine if retinoic acid was playing a role in repair from UVB light, we examined the changes in proliferation and terminal differentiation markers, keratin 6 and loricrin respectively, with disulfiram treatments, ii which inhibit retinoic acid synthesis. We found that retinoic acid synthesis is necessary for normal UVB repair. To further explore the role endogenous retinoids play in the formation and progression of cSCC, we examined STRA6, DHRS9, and ALDH1A1 expression using IHC in all tumor stages of cSCC. We found that these proteins change expression throughout cSCC development and may be contributing to changes in retinoic acid synthesis. Changes in endogenous retinoid metabolism in the progression of cSCC may explain why some retinoid treatments have been effective in treating this cancer. These findings may contribute to the development of more effective prevention and treatments for cSCC. iii Acknowledgments I would like to thank Dr. Helen Everts for her funding, support, and guidance throughout this research project. I would like to thank Dr. Earl Harrison and Dr. Tatiana Oberyszyn for serving on my thesis committee. iv Vita Education 2013-Present……..…………………………….M.S. Human Nutrition, The Ohio State University 2012................................................................B.S. Molecular Genetics, The Ohio State University Experience 2013 to present ..............................................Graduate Teaching Associate, Department of Human Nutrition, The Ohio State University Publications Gressel, K. L., J. F. Duncan, T. M. Oberyszyn, K. M. La Perle, and H. B. Everts, 2015, Endogenous Retinoic Acid Required to Maintain the Epidermis Following Ultraviolet Light Exposure in SKH-1 Hairless Mice:Photochem Photobiol. doi: 10.1111/php.12441 Fields of Study Major Fields: Human Nutrition v Table of Contents Abstract .............................................................................................................................. ii Acknowledgments ............................................................................................................ iv Vita ..................................................................................................................................... v List of Figures ................................................................................................................... ix List of Tables .................................................................................................................... xi Introduction ....................................................................................................................... 1 Chapter 1: Review of Literature ..................................................................................... 3 1.1 Retinol Transport & Metabolism .............................................................................. 3 1.2 Retinoids in the Epidermis ...................................................................................... 12 1.3 Ultraviolet Light ...................................................................................................... 13 1.4 Cell Death ............................................................................................................... 15 1.5 Cell Death and Cornification .................................................................................. 18 1.6 Repair from Ultraviolet Light Exposure ................................................................. 19 1.7 Comparison of Epidermal Models .......................................................................... 20 1.8 Cutaneous Squamous Cell Carcinoma .................................................................... 21 vi 1.9 SKH-1 Hairless Mouse Model ................................................................................ 27 Chapter 2: Endogenous Retinoic Acid Required to Maintain the Epidermis Following Ultraviolet Light Exposure in SKH-1 Hairless Mice ................................. 30 2.1 Introduction ............................................................................................................. 30 2.2 Materials and Methods............................................................................................ 35 2.3 Results ......................................................................................................................... 36 2.31 Altered expression of retinoid metabolism proteins in the upper epidermis and hair follicle remnants 48 hours after UVB treatment ................................................ 36 2.32 Reduced retinoic acid synthesis damaged the upper epidermis after UVB treatment .................................................................................................................... 38 2.4 Discussion ............................................................................................................... 42 Chapter 3: Alterations in Endogenous Retinoid Metabolism in the Progression of Cutaneous Squamous Cell Carcinoma ......................................................................... 46 3.1 Introduction ............................................................................................................. 46 3.2 Materials and Methods............................................................................................ 50 3.3 Results ..................................................................................................................... 52 3.31 Retinoid Metabolism proteins change expression throughout the progression of cSCC .......................................................................................................................... 52 3.32 Retinoid metabolism proteins change expressions between no exposure, acute UVB exposure, and in cSCC and surrounding epidermis. ........................................ 57 vii 3.4 Discussion ............................................................................................................... 59 Chapter 4: Epilogue ........................................................................................................ 64 Appendix: Tables ............................................................................................................ 67 References ........................................................................................................................ 73 viii List of Figures Figure 1. Retinoid Compounds………………………………………………………...31 Figure 2. RA metabolism proteins increase expression in the upper epidermis following UVB treatment……………………………………………………….……...37 Figure 3. Reducing RA synthesis damages the epidermis……………………………40 Figure 4. LOR IHCL changes with disulfiram and UVB treatments……………….41 Figure 5. KRT6 IHCL changes with disulfiram and UVB treatments……...………41 Figure 6. LOR and KRT6 IHCL changes in the lesions and thin epidermis……….42 Figure 7. STRA6 IHCL changes during the progression of cSCC………...………...53 Figure 8. DHRS9 IHCL changes during the progression of cSCC………………….54 Figure 9. Focal and nuclear expression of DHRS9…………………………..……….55 Figure 10. ALDH1A1 IHCL changes during the progression of cSCC……………..56 ix Figure 11. Comparison of undifferentiated and differentiated epidermis and tumors with varying UVB exposure……………………………………………………………58 x List of Tables Table 1. Highest intensity IHCL for STRA6 in uninvolved skin and tumors for specific stages………………………………………...………………………………….67 Table 2. Representative intensity IHCL for STRA6 in uninvolved skin and tumors for specific stages………………………………………………………………………..68 Table 3. Highest intensity IHCL for STRA6 in uninvolved skin and tumors for general stages…………………………………………………………………………..68 Table 4. Representative intensity IHCL for STRA6 in uninvolved
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