Dysregulation of retinoid biosynthesis and metabolism during colon carcinogenesis

The research work presented in this dissertation describes the dysregulation of the retinoid biosynthetic and metabolic pathways accompanying colon carcinogenesis. Colon cancer remains the third leading cause of cancer deaths in the United States. A better understanding of the molecular mechanisms underlying colon tumorigenesis is needed to develop more effective therapies against colon cancer. Chapter 1 is an introduction on colon cancer and retinoids. The relationship between normal intestinal development and progression of colon cancer, including a background on adenomatous polyposis coli (APC) and several colorectal cancer syndromes are presented in the first half of Chapter 1. The latter part is a discussion of retinoid storage, biosynthesis and metabolism. It also summarizes what has been reported about the role of retinoids in normal colon function and their therapeutic effects on various human tumors. Retinol dehydrogenase like (DHRS9) is a colon-specific retinol dehydrogenase that is down-regulated in colon carcinomas. Chapter 2 describes studies that were undertaken to confirm the retinol dehydrogenase activity of DHRS9, demonstrate impairment of the retinoid biosynthetic capabilities of colon carcinoma cells and investigate the possible control of retinoic acid biosynthesis by APC through regulation of DHRS9 expression. A brief description of the retinol dehydrogenase activity of three zebrafish retinol dehydrogenases---rdh1, rdh1l and rdh5, is presented in Chapter 3. A discussion on the regulation of retinoid biosynthesis by APC and the importance of retinoic acid in zebrafish eye and gut development is also included. This is followed by Chapter 4, which describes significant differences in the dysregulation of the retinoid biosynthetic pathway in human colon carcinomas compared to the Apc[min/+ mouse, an established animal model system for studying colon cancer. Chapter 5 shows that the dysregulation of retinoid biosynthesis at multiple points along the pathway is a common occurrence in human colon carcinomas and colon carcinoma cell lines. Studies on cellular retinol binding protein II (CRBPII), its importance in normal intestinal development and retinol uptake are presented as well. Chapter 5 also discusses a broader role for APC in regulating intestinal differentiation by controlling several retinoid biosynthetic components. Conclusions and implications of presented findings are discussed in Chapter 6.