Selenium is a necessary trace element that is incorporated as selenocysteine into selenoproteins via the co-translational modification of transfer RNA-bound serine. Several epidemiological studies have inversely correlated nutritional selenium status and cancer risk, particularly in colon cancer (2). Selenoprotein P (Sepp1) is the only selenoprotein to contain more than one selenocysteine, having 10 incorporated into its primary structure. It is also one of the few selenoproteins still produced during times of severe selenium deficiency (1). It is hypothesized that Selenoprotein P has two main functions based on selenium content: 1) To supply various tissues with selenium, thus allowing in situ generation of selenium containing proteins and 2) a generalized antioxidant function. Such activities suggest that Sepp1 could play a significant role in cancer prevention. In support of this possibility, Sepp1 message is reported to be downregulated in colorectal cancers (3), and single nucleotide polymorphisms (SNPs) in the Selenoprotein P gene (SEPP1) are significantly associated with advanced adenoma risk (4). As such, we postulate that Sepp1 modifies risk for development of colorectal cancer and in particular influences colitis-associated carcinoma which is characterized by increased oxidant stress (5). In order to test the role of selenium and Sepp1 modulation on colon cancer, we propose combining the power of complimentary dietary and murine genetic approaches. Preliminary experiments performed in mice on selenium sufficient and deficient diets indicate that selenium protects from tumorigenesis in mice placed on a colitis associated carcinoma protocol. Interestingly, in preliminary experiments Sepp1 knockout mice placed on the same protocol demonstrated decreased tumor burden compared to wild type mice. This surprising observation begs the question as to which capability is pro-tumorigenic: the selenium transport or enzymatic activity? Future experiments will aim to establish which of the two functional domains of Sepp1 contribute most significantly to tumorigenesis and the mechanisms by which they do so. In order to establish the role of extrahepatic Sepp1 on development of colitis-associated carcinoma, we will place a liver-specific Sepp1 knockout mouse (Sepp1alb-/-) on the colitis-associated carcinoma protocol.
Selenium supplementation has been correlated with decreased cancer risk, though little is known about the mechanisms through which it works. The proposed studies will enhance understanding of the mechanisms by which selenium is able to modify tumor development in a model of colitis-associated carcinoma via the application of rigorously controlled murine genetic approaches. These studies will also determine the role of selenoprotein P, a selenoprotein made even during times of severe selenium deficiency, on colitis-associated carcinoma, establishing the roles of both the antioxidant and selenium transport capabilities of this protein.
