HGF AND TUMOR PROMOTION--A HGF-TRANSGENIC MOUSE MODEL

HGF 与肿瘤促进——HGF 转基因小鼠模型

• 批准号: 2154936
• 负责人: Reza Zarnegar
• 金额: $ 15.87万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-12-10 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2154936
• 关键词: RNase protection assay; biological models; cell growth regulation; chemical carcinogen; chemical carcinogenesis; diethylnitrosamine; enzyme linked immunosorbent assay; gene expression; gene induction /repression; genetically modified animals; growth factor; growth factor receptors; hyperplasia; immunocytochemistry; laboratory mouse; liver cells; liver neoplasms; liver regeneration; molecular oncology; neoplasm /cancer genetics; northern blottings; oncogenes; phenobarbital; preneoplastic state; protooncogene; tissue /cell culture; tumor promoters; western blottings

Cell proliferation and growth is believed to be necessary for promotion of tumors and carcinogenesis. In the case of liver, hepatocyte replication and growth is an essential process during the long period of progression to cancer. Recently, a potent hepatomitogen (Hepatocyte Growth Factor, HGF) has emerged as one of the most likely hepatotrophic agents responsible for maintenance of hepatocyte growth and proliferation. Despite significant progress in characterizing the biochemical and biological properties of HGF, the precise physiological role of this potent epithelial mitogen is unknown in normal and abnormal cell growth. We have generated several lines of transgenic mice harboring a human HGF cDNA under the transcriptional control of mouse Metallothionein 1 promoter. These transgenic animals can provide a suitable model system to further explore the effects of directed high expression of HGF in liver tumor promotion and carcinogenesis induced by different xenobiotics. Utilizing these animals we would like to address the following questions: A) What are the effects of long term and continuous expression of HGF in MT1-HGF transgenic mice in the liver and other tissues? B) Does the chronic overexpression of HGF in MT1-HGF transgenic mice in conjunction with different liver tumor promoters and carcinogens lead to enhanced appearance of pre-neoplastic and neoplastic lesions in the liver of MT1-HGF transgenic mice? C) What are the molecular signals involved in the induction of HGF gene expression in regenerating or xenobiotic treated liver in normal or the MT1-HGF transgenic animals? Answers to these questions may provide further insight to the molecular mechanisms by which tumor promoters and growth factors induce chronic cell proliferation and cancer. Employing techniques and specific molecular probes for HGF detection which are well-established in our laboratory we will analyze the expression of HGF and its receptor (the product of proto-oncogene cMET) in the MT1-HGF transgenic mice treated with or without liver tumor promoters phenobarbital, ciprofibrate, and the carcinogen Diethylnitrosamine to determine whether there is any correlation between the high HGF expression and histopathological abnormalities such as hyperplasia and neoplasia in these animals. The expression of oncogenes c-myc, c-fos, and c-jun which are believed to mediate the mitogenic response of several polypeptide growth factors and also known to be transiently overexpressed during liver regeneration and in some liver tumors (especially c-myc) will be investigated in MT1-HGF transgenic and control mice treated with or without liver tumor promoters. We will also attempt to establish hepatocyte cell lines derived from the neoplastic and normal livers of HGF-transgenic mice which may be suitable for in vitro mutagenesis assays.

据信细胞增殖和生长是促进的必要条件 肿瘤和癌变。 就肝脏而言，肝细胞 复制和增长是长期以来的重要过程 发展为癌症。 最近，有效的肝元素（肝细胞 生长因子，HGF）已成为最有可能的肝营养素之一 负责维持肝细胞生长和 增殖。 尽管在表征 HGF的生化和生物学特性，精确的生理 这种有效的上皮有丝分裂原的作用在正常和异常中尚不清楚 细胞生长。 我们已经生成了几行转基因小鼠 在小鼠的转录控制下携带人类HGF cDNA 金属硫蛋白1启动子。 这些转基因动物可以提供 合适的模型系统，进一步探索了定向高的效果 HGF在肝肿瘤促进和癌变中的表达 不同的异生物学。 利用这些动物我们想解决 以下问题：a）长期的影响和 HGF在肝脏中MT1-HGF转基因小鼠中的连续表达 其他组织？ b）MT1-HGF中HGF的慢性过表达 转基因小鼠与不同的肝肿瘤启动子和 致癌物导致肿瘤前和肿瘤的外观增强 MT1-HGF转基因小鼠的肝脏病变？ c）什么是 参与HGF基因表达诱导的分子信号 在正常或MT1-HGF中再生或异种生物处理的肝脏治疗 转基因动物？ 这些问题的答案可能会进一步提供 洞悉肿瘤启动子和生长的分子机制 因素诱导慢性细胞增殖和癌症。 雇用 HGF检测的技术和特定分子探针 在我们的实验室中建立的良好，我们将分析HGF的表达 MT1-HGF中的受体（原始cmet的乘积） 接受或没有肝肿瘤启动子处理的转基因小鼠 苯巴比妥，电纤维化和致癌二乙基硝基胺至 确定高HGF之间是否存在任何相关性 表达和组织病理学异常，例如增生和 这些动物中的肿瘤。 癌基因c-myc c-fos的表达 据信C-Jun介导了几种有丝分裂的反应 多肽生长因子，也已知瞬时过表达 在肝脏再生和某些肝肿瘤中（尤其是C-MYC） 将在MT1-HGF转基因和对照小鼠中进行研究 或没有肝肿瘤启动子。 我们还将尝试建立 源自肿瘤和正常肝的肝细胞细胞系 可能适合体外诱变的HGF转基因小鼠 测定。