SIGNIFICANCE OF GGT EXPRESSION IN TUMORS

谷氨酰转肽酶(GGT)的表达温度在50到100之间。 是各种癌前病变的正常水平的倍数 上皮组织包括肝、胸、肺和结肠。这个 GGT的生理功能及其在肿瘤形成中的作用 多年来一直是争议的主题。在肝脏中，表达 GGT已被认为是去分化的指标，没有 在肿瘤进展中的功能意义。然而，我们已经提出了 GGT是解毒系统的一部分，使细胞能够 在许多致癌物造成的有毒环境中生存。GGT一直是 被几个实验室克隆。现在可以直接测试我们的 关于GGT功能的假说。我们已经构建了一个 含人GGT基因的表达载体。我们已经将 将DNA导入两个GGT阴性细胞系，获得稳定的转化子。 我们将使用这些行来回答以下问题：表达式 GGT使细胞能够利用细胞外谷胱甘肽作为 半胱氨酸？GGT的表达是否影响细胞内的水平 谷胱甘肽？关于抗氧化剂共识序列的最新报道 基因和该序列在GGT启动子区域的存在 大鼠体内的基因支持GGT是解毒作用的一部分的理论 系统。我们将使用GGT阳性克隆来确定GGT是否正在 作为一组抗氧化基因中的一个被诱导，或者如果它被打开 与其他胎儿基因相关联。如果GGT是戒毒系统的一部分，那么 GGT的表达可能是一种有用的临床标志物 特定药物的治疗效果。我们将使用两种肝细胞 转染人c DNA的细胞株及GGT诱导的肝细胞 用ras诱导，以确定GGT阳性细胞是否对 不同种类的化疗药物。最后，我们计划 研究在肝脏中诱导GGT的物种差异。 GGT在原代培养的大鼠肝细胞中被诱导，但 初步数据表明，它在小鼠肝细胞中不被诱导。 利用大鼠和小鼠肝细胞的原代培养，我们将研究 培养基组分和细胞内谷胱甘肽水平的影响 GGT的诱导。GGT在许多上皮细胞中异常表达 肿瘤。对这种酶及其调节的了解增加可能会 从而改善GGT阳性肿瘤的治疗。

The enzyme gamma-glutamyl transpeptidase (GGT) is expressed at 50 to 100 times the normal level in preneoplastic lesions from a variety of epithelial tissues including liver, breast lung and colon. The physiological function of GGT and the role it may play in tumor formation have been subjects of controversy for many years. In the liver, expression of GGT has been viewed as an indicator of dedifferentiation with no functional significance in tumor progression. However, we have proposed that GGT is part of a detoxification system that enables the cells to survive in the toxic environment created by many carcinogens. GGT has been cloned by several laboratories. It is now possible to directly test our hypothesis regarding the function of GGT. We have constructed an expression vector containing the cDNA for human GGT. We have transfected the DNA into two GGT-negative cell lines and obtained stable transformants. We will use these lines to answer the following questions: Does expression of GGT enable cells to use extracellular glutathione as a source of cysteine? Does expression of GGT effect the intracellular level of glutathione? The recent report of a consensus sequence for antioxidant genes and the presence of this sequence in the promoter region of the GGT gene in the rat supports the theory that GGT is part of a detoxification system. We will use GGT-positive clones to determine whether GGT is being induced as one of a set of antioxidant genes or if it is being turned on with other fetal genes. If GGT is part of a detoxication system than expression of GGT may be a useful clinical marker in predicting the therapeutic efficacy of specific drugs. We will use both the liver cell lines transfected with human cDNA and the liver cells in which GGT has been induced with ras to determine whether GGT-positive cells are more resistant to various classes of chemotherapeutic agents. Finally, we plan to investigate the species differences in the induction of GGT in the liver. GGT is induced in rat hepatocytes when they are put in primary culture but preliminary data indicates that it is not induced in mouse hepatocytes. Using primary cultures of rat and mouse hepatocytes we will investigate the effect of media components and the intracellular level of glutathione on the induction of GGT. GGT is aberrantly expressed in many epithelial tumors. An increased understanding of this enzyme and its regulation may lead to improved treatment of GGT-positive tumors.