Genomic and Genetic Analysis of Hepatic Tumor Promotion

描述（由申请人提供）：雄性小鼠比雌性小鼠更容易患自发性肝癌以及多种致癌物诱发的肝肿瘤。这种性别差异是性激素对肝癌发生的相反作用的结果：雄激素促进癌前病变的发展，而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在小鼠中诱发肝肿瘤的化学物质的一个重要子集在雌性中优先活跃。我们实验室最近的工作确定了 17 号染色体上的一个特定位点 Hcfl，该位点消除了女性荷尔蒙环境对肝脏肿瘤发展的抑制作用。我们将检验以下假设：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过程中诱导常见的信号通路。首先，将比较雌性特异性肝癌物质，包括 5,5-二苯乙内酰脲、黄樟素和伏马菌素 BI，以及在两性中均具有促进作用的药物，例如 HBB 和 WY-14,643，将比较它们在雌性 C57BL/6J 和同系 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 将使用肝脏特异性 cDNA 微阵列进行分析，以阐明基因表达改变的常见模式。其次，通过对激光捕获显微切割分离的组织制备的 cDNA 进行微阵列分析，对由这些药物促进的表型不同类别的癌前病变进行比较。最后，Hcfl 基因座的分子身份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.