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发生自发性肝癌和多种致癌物诱导的肝脏肿瘤。这种性别差异是性激素对肝癌发生的相反作用的结果：雄激素促进肿瘤前病变的发展，而卵巢激素抑制肿瘤前病变的发展。然而，国家毒理学计划发现，在小鼠中诱导肝脏肿瘤的化学物质的重要亚群优先在雌性中活跃。我们实验室最近的工作导致鉴定了17号染色体Hcfl上的一个特定位点，该位点消除了女性激素环境对肝脏肿瘤发展的抑制作用。我们将验证在雌性小鼠中特异性诱导肝脏肿瘤的Hcfl和化学物质在促进肝癌发生过程中诱导共同信号通路的假设。首先，比较女性特异性肝癌致癌物，包括5,5-二苯基海英酮、黄樟酚和富马菌素BI，以及在两性中都有启动子活性的药物，如HBB和wey - 14643，在雌性C57BL/6J和基因Hcfl小鼠中的促进活性。用这些药物治疗12周的动物肝脏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解剖分离的组织制备的cDNA进行微阵列分析，比较这些药物引起的不同表型的癌前病变。最后，通过定位克隆确定Hcfl基因座的分子特性。

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.