MECHANISMS OF HEPATIC TUMOR PROMOTION BY PCB'S

众所周知，多氯联苯(PCbs)是啮齿动物肝细胞癌的有效诱导剂。多氯联苯混合物和单独的多氯联苯聚集剂都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，这些制剂正在增加肝脏的氧化应激，这可能会导致脂质过氧化、氧化性DNA损伤或基因表达的变化。一些转录因子，包括核因子-kappaB和AP-1，可以至少部分地被氧化应激激活。我们已经证明，多氯联苯增加了肝脏核因子-kappaB和AP-1的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在多氯联苯的促进活性中起重要作用的假设。我们将研究1)多氯联苯激活NF-kappaB和AP-1的机制，如氧化应激增加；2)肝脏枯否细胞在多氯联苯激活核因子-kappaB和AP-1、诱导细胞增殖和促进癌前病变中的重要性；3)通过分析多氯联苯后这些转录因子的下游靶标来分析核因子-kappaB激活的后果；以及4)如果失去p50亚单位的NF-kappaB将影响多氯联苯的促进活性。这些研究将揭示核因子-kappaB激活是否是多氯联苯促进活性所必需的，并将阐明核因子-kappaB激活影响多氯联苯促进肝肿瘤的机制。

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.