Genomic and Genetic Analysis of Hepatic Tumor Promotion

肝脏肿瘤促进的基因组和遗传学分析

• 批准号: 6928590
• 负责人: Norman R. Drinkwater
• 金额: $ 28.92万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-08 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928590
• 关键词: androgens; biological signal transduction; carcinogenesis; carcinogens; complementary DNA; estrogens; gender difference; gene expression; laboratory mouse; liver neoplasms; messenger RNA; molecular cloning; neoplasm /cancer genetics; neoplastic process; northern blottings; polymerase chain reaction; progesterone; tumor promoters

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.

描述（由申请人提供）：雄性小鼠比女性更容易受到自发肝癌的影响，并通过多种致癌物诱导肝肿瘤。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，而卵巢激素抑制了癌性病变的发展，但是，由国民毒理学计划诱导小鼠诱导小鼠肝肿瘤的大量化学物质在女性中诱导小鼠肿瘤。我们实验室的最新工作导致鉴定了17号染色​​体HCFL的特定基因座，该基因座消除了女性激素环境对肝肿瘤发育的抑制作用。我们将检验以下假设：在促进肝癌发生期间，HCFL和专门诱导雌性小鼠肝肿瘤的化学物质会诱导共同的信号通路。首先，包括5,5-二苯基氢化，safrole和富莫诺蛋白BI，以及活跃在男女中的启动子（例如HBB和WY-14,643）中的雌性肝癌素，以及在女性C57BL/6J和Concantic Hcfl Mice中的促进活动。将使用肝脏特异性的cDNA微阵列分析接受这些药物处理12周的动物的肝mRNA，以阐明基因表达改变的常见模式。其次，通过这些药物促进的表型不同类别的肿瘤性病变，将通过对通过激光捕获微截止分离的组织制备的cDNA进行比较。最后，HCFL基因座的分子身份将由位置克隆确定。