EARLY EVENTS IN CHEMICALLY INDUCED RAT HEPATOCARCINOGENESIS

化学诱导的大鼠肝癌的早期事件

• 批准号: 4692371
• 负责人: P J WIRTH
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/4692371
• 关键词: DNA; cell population study; cell type; chemical carcinogenesis; cyclic amine; cytoplasm; disease /disorder model; gel electrophoresis; gene expression; high performance liquid chromatography; liver cells; liver neoplasms; neoplasm /cancer genetics; nucleoside monophosphate; preneoplastic state; radiotracer; tissue /cell culture

The project was initiated to study the sequence of events during chemically induced neoplasia using the rodent hepatoma model in combination with quantitative two-dimensional electrophoresis (2-D). Results obtained to date include: 1) demonstration that 2-D could reliably detect and quantitate changes in known polypeptide markers for hepatocarcinogernesis (albumin, alpha-fetoprotein, aldehyde dehydrogenase, the individual subunits [Yc, Yb, Ya, and Yp] of the glutathione-S-transferases [B, A, ligandin and P] and DT-diaphorase). 2) Using the Solt-Farber initiation promotion protocol, preneoplastic and neoplastic liver nodules were induced in male Fischer F344 rats. Individual nodules were dissected and classified histologically as being either early preneoplastic, preneoplastic, or neoplastic. One cytosolic polypeptide (pI 6.8/57 kDa) and three membrane-associated polypeptides (pI 6.25/41 kDa; 6.75/26 kDa; 6.05/21 kDa) were expressed in both preneoplastic and neoplastic nodules but not in control liver. In addition to quantitation of the above known markers, numerous quantitative changes were also detected in as yet unidentified polypeptides among the various cell types. Twenty-one membrane and 10 cytosolic polypeptides were down-regulated, while 14 membrane and 6 cytosolic polypeptides were up-regulated during hepatocarcino-genesis. In all but three polypeptides, the direction and magnitude of change were the same in both preneoplastic and neoplastic nodules. 3) Investigation of the homogeneity and heterogeneity of polypeptide expression among individual nodules isolated from separate animals have revealed marked similarities among the individual preneoplastic and neoplastic nodules from the same animal and among nodules isolated from different animals.

该项目的启动是为了研究化学过程中的事件顺序， 使用啮齿类动物肝癌模型联合 定量双向电泳（2-D）。 取得的成果， 数据包括：1）证明2-D可以可靠地检测， 肝癌发生的已知多肽标记物的定量变化 （白蛋白，甲胎蛋白，醛脱氢酶，个体 谷胱甘肽-S-转移酶[B，A， 配体素和P]和DT-心肌黄酶）。 2)利用索尔特-法伯启动 促进方案，诱导癌前和肿瘤性肝结节 在雄性Fischer F344大鼠中。 解剖单个结节， 在组织学上分类为早期癌前病变， 肿瘤前或肿瘤性。 一种胞质多肽（pI 6.8/57 kDa） 和三种膜结合多肽（pI 6.25/41 kDa; 6.75/26 kDa; 6.05/21 kDa）在癌前和肿瘤结节中均有表达 但在对照肝脏中没有。 除了定量上述已知的 标记物，许多数量变化也检测到， 在各种细胞类型中存在未鉴定的多肽。 二十一 膜和10个胞质多肽下调，而14个 细胞膜和6种胞质多肽在 肝癌发生 在除了三种多肽之外的所有多肽中，方向和 在肿瘤前和肿瘤中，变化幅度相同 结节 3)的同质性和异质性的研究 从分离的单个根瘤中分离的多肽表达 动物们已经揭示了个体之间的显著相似性 来自同一动物和结节之间的癌前和肿瘤结节 分离自不同的动物。