EARLY EVENTS IN CHEMICALLY INDUCED RAT HEPATOCARCINOGENESIS

化学诱导的大鼠肝癌的早期事件

• 批准号: 3963468
• 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/3963468
• 关键词: cell population study; cell type; chemical carcinogenesis; clofibrate; cyclic amine; cytoplasm; disease /disorder model; gel electrophoresis; gene expression; glutathione transferase; high performance liquid chromatography; liver cells; liver metabolism; liver neoplasms; neoplasm /cancer genetics; oncoproteins; 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 gel electrophoresis (2D-PAGE). Results obtained to date include: (1) analysis of polypeptide differences between normal rat liver and preneoplastic and neoplastic nodules generated using either the Solt-Farber regimen ("resistant hepatocyte" model) or via feeding the nongenotoxic inducer of peroxisome proliferation, ciprofibrate, revealed few qualitative but numerous quantitative polypeptide differences; (2) polypeptide expression in individual preneoplastic and neoplastic nodules induced via the Solt-Farber protocol or with ciprofibrate was very similar, suggesting a marked "homogeneity" rather than "heterogeneity" of polypeptide expression among the early lesions; (3) all Solt-Farber generated nodules stained strongly both for gamma-gutamyltranspeptidase (GGT) activity and for the placental form of glutathione-S-transferase (GST-P), while in the ciprofibrate induced nodules the expression of GGT and s GST-P was not significantly different than control liver levels; (4) four qualitative polypeptide differnces were noted in Solt-Farber-induced nodules as compared to normal liver. Two of these, polypeptides B (pI 6.25/41 kDa) and C (pI 6.75/24 kDa) were expressed in both ciprofibrate-induced and Solt-Farber-generated preneoplastic and neoplastic nodules. In addition five membrane-associated (5.25/59 kDa, 5/30/33 kDa, 5.25/27 kDa, 6.82/23.5 kDa, and 6.75/21 kDa) and four cytosolic polypeptides (6.20/45 kDa, 5/85/36 kDa, 5.06/34 kDa, 6.00/24 kDa) were coordinately expressed in both preneoplassic and neoplastic nodules from both ciprofibrate and Solt-Farber hepatocarcinogenesis models.

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 定量双向凝胶电泳（2D-PAGE）。 结果 迄今为止获得的结果包括：（1）分析 正常大鼠肝脏和肿瘤前和肿瘤结节产生， Solt-Farber方案（“抗性肝细胞”模型）或通过 喂食过氧化物酶体增殖的非遗传毒性诱导剂，环丙贝特， 揭示了很少的定性但大量的定量多肽差异; (2)个体肿瘤前和肿瘤中的多肽表达 通过Solt-Farber方案或环丙贝特诱导的结节非常 类似，表明一个显着的“同质性”，而不是“异质性”的 多肽表达的早期病变;（3）所有Solt-Farber 生成的结节对γ-谷氨酰转肽酶和 (GGT)活性和胎盘型谷胱甘肽-S-转移酶 而在环丙贝特诱导的结节中， 与对照组相比，sGST-P无显著性差异; 在Solt-Farber诱导的细胞中观察到四种定性多肽差异， 与正常肝脏相比。 其中两种，多肽B（pI pI 6.75/24 kDa）和C（pI 6.25/41 kDa）在两种细胞中均有表达。 环丙贝特诱导的和Solt-Farber产生的癌前病变和肿瘤 结节 此外，五种膜相关蛋白（5.25/59 kDa，5/30/33 kDa， 5.25/27 kDa、6.82/23.5 kDa和6.75/21 kDa）和四种细胞溶质 多肽（6.20/45 kDa，5/85/36 kDa，5.06/34 kDa，6.00/24 kDa）是 在肿瘤前和肿瘤结节中协调表达， 环丙贝特和Solt-Farber肝癌发生模型。