MECHANISMS OF HEPATIC TUMOR PROMOTION BY PCB'S

PCB促进肝肿瘤的机制

• 批准号: 6457649
• 负责人: HOWARD P GLAUERT
• 金额: $ 14.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6457649
• 关键词: DNA damage; cell proliferation; chemical carcinogenesis; environment related neoplasm /cancer; environmental toxicology; gene environment interaction; gene targeting; genetically modified animals; halobiphenyl /halotriphenyl compound; hazardous substances; laboratory mouse; laboratory rat; liver neoplasms; neoplasm /cancer genetics; oxidative stress; tissue /cell culture; toxin metabolism; transcription factor; tumor promoters

It is well established that polychlorinated biphenyls (PCBs) are efficacious inducers of hepatocellular carcinomas in rodents. Both PCB mixtures and individual PCB congers have promoting activity in two- stage hepatocarcinogenesis, but the mechanism of their promoting activity is unclear. One possible mechanism is that these agents are increasing oxidative stress in the liver, which could lead to lipid peroxidation, oxidative DNA damage, or changes in gene expression. Several transcription factors, including NF-kappaB and AP-1, can be activated at least in part by oxidative stress. We have shown that PCBs increase the hepatic DNA binding activities of both NF-kappaB and AP- 1, particularly after chronic administration. In this project we propose to test the hypothesis that these transcription factors are important in the promoting activity of PCBs. We will examine 1) the mechanisms, such as increased oxidative stress, by which PCBs activated NF-kappaB and AP- 1; 2) the importance of hepatic Kupffer cells in the activation of NF- kappaB and AP-1, the induction of cell proliferation, and the promotion of pre-neoplastic lesions by PCBs; 3) the consequences of NF-kappaB activation by analyzing downstream targets of these transcription factors after the administration of PCBs; and 4) if the loss of the p50 subunit of NF-kappaB will influence the promoting activity of PCBs. These studies will show if NF-kappaB activation is necessary for the promoting activity of PCBs and will elucidate the mechanism by which NF-kappaB activation influences hepatic tumor promotion by PCBs.

众所周知，多氯联苯 (PCB) 是啮齿类动物肝细胞癌的有效诱导剂。 PCB混合物和单独的PCB海鳗均具有促进两阶段肝癌发生的活性，但其促进活性的机制尚不清楚。一种可能的机制是这些药物会增加肝脏的氧化应激，从而导致脂质过氧化、DNA 氧化损伤或基因表达的变化。包括 NF-kappaB 和 AP-1 在内的多种转录因子至少可以部分被氧化应激激活。我们已经证明 PCB 可以增加 NF-κB 和 AP-1 的肝 DNA 结合活性，特别是在长期给药后。在这个项目中，我们建议检验这些转录因子对于促进 PCB 活性很重要的假设。我们将研究 1) PCB 激活 NF-kappaB 和 AP-1 的机制，例如增加氧化应激； 2）肝库普弗细胞在激活NF-κB和AP-1、诱导细胞增殖以及PCB促进肿瘤前期病变中的重要性； 3) 通过分析施用 PCB 后这些转录因子的下游靶点，NF-kappaB 激活的后果； 4) NF-kappaB p50亚基的缺失是否会影响PCBs的促进活性。这些研究将表明 NF-kappaB 激活对于 PCB 的促进活性是否是必要的，并将阐明 NF-kappaB 激活影响 PCB 促进肝肿瘤的机制。