Genomic and Genetic Analysis of Hepatic Tumor Promotion

描述（由申请方提供）：雄性小鼠比雌性小鼠更易患自发性肝癌和多种致癌物诱导的肝肿瘤。这种性别差异是性激素对肝癌发生的相反作用的结果：雄激素促进，卵巢激素抑制，癌前病变的发展，然而，国家毒理学计划发现诱导小鼠肝肿瘤的化学物质的一个重要子集优先在女性中活跃。我们实验室最近的工作已经鉴定了17号染色体上的一个特定位点，Hcfl，它消除了女性激素环境对肝脏肿瘤发展的抑制作用。我们将测试这一假设，即Hcfl和化学物质，特别是诱导雌性小鼠肝肿瘤诱导共同的信号通路，在促进肝癌的发生。首先，将比较雌性特异性肝癌原，包括5，5-二苯基乙内酰脲、黄樟素和伏马菌素BI，以及在两种性别中作为促进剂的活性剂，如HBB和WY-14，643，在雌性C57 BL/6 J和同源Hcfl小鼠中的促进活性。将使用肝脏特异性cDNA微阵列分析用这些药物治疗12周的动物的肝脏mRNA，以阐明基因表达改变的常见模式。第二，通过对从激光捕获显微切割分离的组织中制备的cDNA进行微阵列分析，比较由这些药物促进的表型不同的肿瘤前病变类别。最后，通过定位克隆确定Hcfl基因座的分子同一性。

DESCRIPTION (provided by applicant): Male mice are more susceptible than females to spontaneous liver cancer and to the induction of liver tumors by a wide variety of carcinogens. This sex difference is a consequence of the opposing effects of sex hormones on hepatocarcinogenesis: androgens promote, and ovarian hormones inhibit, the development of preneoplastic lesions, However, a significant subset of the chemicals found to induce liver tumors in mice by the National Toxicology Program are preferentially active in females. Recent work from our laboratory has led to the identification of a specific locus on Chromosome 17, Hcfl, that abrogates the inhibitory effect of the female hormonal environment on liver tumor development. We will test the hypothesis that Hcfl and chemicals that specifically induce liver tumors in female mice induce common signaling pathways during promotion of hepatocarcinogenesis. First, female-specific hepatocarcinogens, including 5,5-diphenylhydantoin, safrole, and Fumonisin BI, and agents active as promoters in both sexes, such as HBB and WY-14,643, will be compared for their promoting activities in female C57BL/6J and congenic Hcfl mice. Hepatic mRNA from animals treated for 12 weeks with these agents will be analyzed using liver-specific, cDNA microarrays in order to elucidate common patterns of altered gene expression. Second, phenotypically distinct classes of preneoplastic lesions promoted by these agents will be compared by microarray analysis of cDNA prepared from tissue isolated by laser capture micro-dissection. Finally, the molecular identity of the Hcfl locus will be determined by positional cloning.