Role of Selenium in Cancer and Health

硒被认为是一种化学预防剂，可以预防各种形式的癌症（如结肠癌、前列腺癌、肺癌和肝癌）、心脏病和抗病毒药物。这一因素也可能在延缓衰老过程、延缓艾滋病毒阳性患者的艾滋病进展、免疫功能、哺乳动物发育和男性生殖方面发挥作用。这种元素的有益作用至少部分是由于它作为氨基酸硒半胱氨酸（Sec）存在于硒蛋白中。我们的计划侧重于Sec被纳入蛋白质的手段和特定硒蛋白在人体健康中的作用。由于Sec tRNA是唯一已知的调控硒蛋白表达的tRNA，因此，我们生产了编码突变Sec tRNA基因的转基因小鼠，生产了缺乏Sec tRNA基因的小鼠（即标准Sec tRNA基因敲除小鼠），生产了携带Sec tRNA基因条件敲除的小鼠作为调节硒蛋白合成的模型系统，并使用RNAi敲除了几个硒蛋白并产生了RNAi小鼠，因此，评估这些含硒蛋白质对健康的作用。我们产生了携带突变的Sec tRNA基因的转基因小鼠系，其反密码子的摆动位置有T -> a碱基变化，或a -> G碱基在37位置发生变化。这两种突变的trna以蛋白质和组织特异性的方式改变硒蛋白的生物合成。我们现在正在研究这些小鼠系对病毒感染、致癌物和含有不同水平硒的饮食的反应，这些硒是一种编码癌症驱动基因的遗传背景。我们已经用携带野生型Sec tRNA基因的转基因小鼠拯救了标准Sec tRNA基因敲除小鼠，这些小鼠胚胎致死，目前正在分析哪些硒蛋白被拯救。利用loxP-Cre技术，我们将条件敲除小鼠与不同的Cre小鼠配对，选择性地去除肝、前列腺、脑和乳腺等多种组织中的Sec tRNA基因（从而改变硒蛋白的表达）。通过这种方式，我们可以评估硒蛋白在肝脏、前列腺、脑和乳腺恶性肿瘤中的作用。在过去的一年里，我们完全敲除了肝脏中硒蛋白的表达，并表明硒蛋白的表达对正常的肝功能至关重要。在研究特定硒蛋白在人类健康中的作用时，我们之前观察到15 kDa硒蛋白的几个特征与癌症病因之间的相关性。我们培育了一只基因敲除小鼠，并正在研究从小鼠基因组中去除该基因的后果。我们利用RNA干扰（RNAi）技术对果蝇中的一种硒蛋白进行了特异性去除，还利用RNAi技术敲低了哺乳动物组织中的硒蛋白SelH，并制造了SelH转基因小鼠，目前正在分析去除SelH在小鼠中的表达的结果。上述每项研究都旨在了解含硒蛋白质在健康中的作用。

Selenium is recognized as a chemopreventive agent against various forms of cancer (e.g., colon, prostate, lung and liver), against heart disease, and as an antiviral agent. This element also likely plays a role in delaying the aging process, in delaying the progression of AIDS in HIV positive patients, in immune function, in mammalian development and in male reproduction. The beneficial effects of this element are due, at least in part, to its presence in selenoproteins as the amino acid, selenocysteine (Sec). Our program focuses on the means by which Sec is incorporated into protein and the role of specific selenoproteins in human health. As Sec tRNA is the only known tRNA to govern the expression of an entire class of proteins, the selenoproteins, we produced transgenic mice encoding mutant Sec tRNA transgenes, produced mice lacking the Sec tRNA gene (i.e., the standard Sec tRNA gene knockout mouse), produced mice carrying a conditional knockout of the Sec tRNA gene as model systems to modulate selenoprotein synthesis and using RNAi have knocked down several selenoproteins and generated a RNAi mouse, and therefore, assess the roles of these selenium-containing proteins in health. We generated transgenic mouse lines carrying mutant Sec tRNA transgenes that have either a T -> A base change in the wobble position of the anticodon or an A -> G base change at position 37. Both mutant tRNAs alter selenoprotein biosynthesis in a protein and tissue specific manner. We are now examining these mouse lines to respond to viral infection, to carcinogens and to diets with varying levels of selenium in a genetic background encoding a cancer driver gene. We have rescued standard Sec tRNA gene knockout mice that are embryonic lethal with transgenic mice carrying wild type Sec tRNA transgenes and are presently analyzing which selenoproteins are rescued. Using loxP-Cre technology, we have mated the conditional knockout mice with different Cre mice to selectively remove the Sec tRNA gene (and therefore alter selenoprotein expression) in various tissues including liver, prostate, brain and breast. In this way, we can assess the role of selenoproteins in liver, prostate, brain and breast malignancies. This past year we have totally knocked out selenoprotein expression in liver and have shown that selenoprotein expression is essential of normal liver function. In studies examining the role of specific selenoproteins in human health, we previously observed a correlation between several characteristics of the 15 kDa selenoprotein (Sep15) and cancer etiology. We generated a knockout mouse and are examining the consequences of removing this gene from the mouse genome. We completed an analysis of one selenoprotein in Drosophila using RNA interference (RNAi) to specifically remove it, have also knocked down a selenoprotein, SelH, in mammalian tissue using RNAi and made a RNAi transgenic mouse of SelH, and are analyzing the consequences of removing SelH expression in mice. Each of the above studies is directed at understanding the roles of selenium-containing proteins in health.