SIGNIFICANCE OF GGT EXPRESSION IN TUMORS

GGT 表达在肿瘤中的意义

• 批准号: 3201874
• 负责人: MARIE H HANIGAN
• 金额: $ 14.43万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3201874
• 关键词: alkylating agents; alpha fetoprotein; antineoplastics; antioxidants; biomarker; clone cells; cyclophosphamide; cysteine; detoxification; drug resistance; enzyme induction /repression; genetic regulation; glutathione; glutathione transferase; histochemistry /cytochemistry; laboratory mouse; laboratory rat; liver cells; methionine; molecular oncology; neoplasm /cancer genetics; oncogenes; protein glutamine gamma glutamyltransferase; radiotracer; southern blotting; species difference; tissue /cell culture; transfection

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.

酶γ-谷氨酰转肽酶（GGT）在50至100 倍正常水平的肿瘤前病变从各种 上皮组织，包括肝脏、乳腺、肺和结肠。 的 GGT的生理功能及其在肿瘤形成中的作用 多年来一直备受争议 在肝脏中，表达 GGT的水平被视为去分化的指标， 在肿瘤进展中的功能意义。 但是，我们建议 GGT是解毒系统的一部分， 在由许多致癌物质造成的有毒环境中生存。 GGT已经 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。 我们建立了一个 含有人GGT cDNA的表达载体。 我们已经将 将该DNA导入两个GGT阴性细胞系中并获得稳定的转化子。 我们将使用这些行来回答以下问题： 使细胞能够利用细胞外谷胱甘肽作为来源， 半胱氨酸？ GGT的表达是否影响细胞内的 谷胱甘肽？ 一个抗氧化剂共有序列的最新报道 基因和该序列在GGT启动子区的存在 大鼠中的一种基因支持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是否被 作为一组抗氧化基因之一被诱导， 与其他胎儿基因结合 如果GGT是解毒系统的一部分， GGT的表达可能是一个有用的临床指标， 具体药物的疗效。 我们将利用肝细胞 用人cDNA转染的细胞系和其中GGT已被转染的肝细胞， 用ras诱导，以确定GGT阳性细胞是否更耐药 涉及各种类型的化疗剂。 最后，我们计划 研究肝脏中GGT诱导的物种差异。 当大鼠肝细胞被置于原代培养物中时， 初步数据表明，它在小鼠肝细胞中不被诱导。 使用大鼠和小鼠肝细胞的原代培养物，我们将研究 培养基成分和细胞内谷胱甘肽水平对 GGT的诱导。 GGT在许多上皮细胞中异常表达， 肿瘤的 对这种酶及其调节的进一步了解可能 导致GGT阳性肿瘤治疗的改善。