Genomic and Genetic Analysis of Hepatic Tumor Promotion

描述(申请人提供)：雄性小鼠比雌性小鼠更容易患自发性肝癌和多种致癌物质诱发的肝癌。这种性别差异是性激素对肝癌发生的相反作用的结果：雄激素促进癌前病变的发展，卵巢激素抑制癌前病变的发展，然而，国家毒理学计划发现的诱导小鼠肝脏肿瘤的化学物质中的一个重要子集优先在雌性中起作用。我们实验室最近的工作导致在17号染色体上发现了一个特定的基因位点，Hcf1，它消除了女性激素环境对肝脏肿瘤发展的抑制作用。我们将检验这一假设，即Hcfl和特异性诱导雌性小鼠肝肿瘤的化学物质在促进肝癌发生的过程中诱导共同的信号通路。首先，将比较雌性特有的致癌物，包括5，5-二苯基海因、黄樟素和伏马菌素BI，以及两性中作为启动子的活性物质，如HBB和WY-14,643，比较它们在雌性C57BL/6J和同源Hcfl小鼠中的促进活性。使用这些药物治疗12周的动物的肝脏mRNA将使用肝脏特异的cDNA微阵列进行分析，以阐明基因表达变化的常见模式。其次，通过对激光捕获显微切割分离的组织中制备的基因进行微阵列分析，比较由这些药物促进的表型不同类别的癌前病变。最后，Hcf1基因座的分子同一性将通过定位克隆来确定。

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.