Selenium and Selenoprotein P Modify Colorectal Tumorigenesis

说明(申请人提供)：硒是一种必需的微量元素，通过转移RNA结合的丝氨酸的共翻译修饰，以硒半胱氨酸的形式并入硒蛋白中。一些流行病学研究发现，营养硒状况与癌症风险呈负相关，尤其是在结肠癌中(2)。硒蛋白P(Sepp1)是唯一一种含有一种以上硒半胱氨酸的硒蛋白，其一级结构中含有10个硒半胱氨酸。它也是在严重缺硒时期仍然产生的少数硒蛋白之一(1)。根据硒的含量推测，硒蛋白P有两个主要功能：1)向各种组织供应硒，从而允许原位生成含硒蛋白；2)广泛的抗氧化功能。这些活动表明，Sepp1可能在癌症预防中发挥重要作用。为了支持这一可能性，有报道称Sepp1信息在结直肠癌中下调(3)，而硒蛋白P基因(SEPP1)的单核苷酸多态(SNPs)与晚期腺瘤风险显著相关(4)。因此，我们推测Sepp1改变了结直肠癌发生的风险，尤其是影响了以氧化应激增加为特征的结肠炎相关癌(5)。为了测试硒和Sepp1对结肠癌的调节作用，我们建议结合补充饮食和小鼠遗传方法的力量。在小鼠身上进行的初步实验表明，硒对服用结肠炎相关癌症方案的小鼠的肿瘤形成具有保护作用。有趣的是，在初步实验中，与野生型小鼠相比，采用相同方案的Sepp1基因敲除小鼠显示出较低的肿瘤负担。这一令人惊讶的观察结果回避了一个问题，即哪种能力是促肿瘤的：硒运输还是酶活性？未来的实验将致力于确定Sepp1的两个功能结构域中的哪一个对肿瘤发生最有意义，以及它们发挥作用的机制。为了确定肝外Sepp1在结肠炎相关癌发生发展中的作用，我们将肝脏特异性Sepp1基因敲除小鼠(Sepp1alb-/-)置于结肠炎相关癌方案中。 与公共健康相关：补硒与降低癌症风险相关，尽管人们对其作用机制知之甚少。这项拟议的研究将通过应用严格控制的小鼠遗传方法，加强对硒能够改变结肠炎相关癌模型中肿瘤发展的机制的理解。这些研究还将确定硒蛋白P在结肠炎相关癌症中的作用，确定这种蛋白的抗氧化剂和硒运输能力的作用。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.