Selenium and Selenoprotein P Modify Colorectal Tumorigenesis

硒和硒蛋白 P 改变结直肠肿瘤发生

基本信息

  • 批准号:
    8312167
  • 负责人:
  • 金额:
    $ 2.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-05-01 至 2014-04-30
  • 项目状态:
    已结题

项目摘要

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.
描述(由申请人提供):硒是一种必需的微量元素,通过转移RNA结合丝氨酸的共翻译修饰以硒代半胱氨酸形式掺入硒蛋白中。一些流行病学研究发现,营养硒状态与癌症风险呈负相关,特别是在结肠癌中(2)。硒蛋白P(Sepp 1)是唯一一种含有一个以上硒代半胱氨酸的硒蛋白,其一级结构中含有10个硒代半胱氨酸。它也是在严重缺硒时期仍然产生的少数硒蛋白之一(1)。据推测,硒蛋白P具有基于硒含量的两个主要功能:1)向各种组织供应硒,从而允许原位产生含硒蛋白质和2)普遍的抗氧化功能。这些活动表明Sepp 1可能在癌症预防中发挥重要作用。为了支持这种可能性,据报道Sepp 1信息在结直肠癌中下调(3),并且硒蛋白P基因(SEPP 1)中的单核苷酸多态性(SNP)与晚期腺瘤风险显着相关(4)。因此,我们假设Sepp 1改变结直肠癌的发展风险,特别是影响结肠炎相关癌,其特征是氧化应激增加(5)。为了测试硒和Sepp 1调节对结肠癌的作用,我们建议结合互补饮食和小鼠遗传方法的力量。在硒充足和缺乏饮食的小鼠中进行的初步实验表明,硒保护置于结肠炎相关癌方案的小鼠免于肿瘤发生。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Sepp 1敲除小鼠显示出肿瘤负荷降低。这一令人惊讶的观察回避了这样一个问题,即哪种能力是促肿瘤的:硒的转运或酶活性?未来的实验将旨在确定Sepp 1的两个功能结构域中哪一个对肿瘤发生的贡献最大,以及它们这样做的机制。为了确定肝外Sepp 1在结肠炎相关癌发展中的作用,我们将在结肠炎相关癌方案中放置肝脏特异性Sepp 1敲除小鼠(Sepp 1alb-/-)。 公共卫生关系:补充硒与降低癌症风险相关,但人们对其作用机制知之甚少。拟议的研究将提高硒能够通过应用严格控制的小鼠遗传方法在结肠炎相关癌模型中改变肿瘤发展的机制的理解。这些研究还将确定硒蛋白P的作用,即使在严重缺硒的情况下也会产生硒蛋白,对结肠炎相关癌的作用,建立这种蛋白的抗氧化和硒转运能力的作用。

项目成果

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Caitlyn W Barrett其他文献

49 BVES Suppresses Inflammatory Carcinogenesis
  • DOI:
    10.1016/s0016-5085(13)60045-1
  • 发表时间:
    2013-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Bobak Parang;Andrew Kaz;Yash A. Choksi;Elizabeth McDonough;Shenika Poindexter;Caitlyn W Barrett;Amber Bradley;Wei Ning;Vishruth K. Reddy;Kay Washington;Frank Revetta;J. Joshua Smith;Xi Chen;Keith T. Wilson;Thomas Brand;William M. Grady;Christopher S. Williams
  • 通讯作者:
    Christopher S. Williams

Caitlyn W Barrett的其他文献

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{{ truncateString('Caitlyn W Barrett', 18)}}的其他基金

Selenium and Selenoprotein P Modify Colorectal Tumorigenesis
硒和硒蛋白 P 改变结直肠肿瘤发生
  • 批准号:
    8473051
  • 财政年份:
    2012
  • 资助金额:
    $ 2.82万
  • 项目类别:

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