Identification of Tumor Promotion Susceptibility Genes

促癌易感基因的鉴定

• 批准号: 8191037
• 负责人: John DiGiovanni
• 金额: $ 33.52万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-18 至 2013-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191037
• 关键词: Acetates; Acetone; Affect; Animal Model; Animals; Applications Grants; C57BL/6 Mouse; Chromosome Mapping; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 9; Congenic Mice; Congenic Strain; DBA/2 Mouse; Data; Development; Differentiation and Growth; Disease; Environmental Carcinogens; Epidemiology; Epidermis; Epithelial; Gene Expression; Gene-Modified; General Population; Generations; Genes; Genetic; Genetic Polymorphism; Glutathione S-Transferase; Goals; Haplotypes; Health; Human; Inherited; Knock-in Mouse; Lead; Link; Lipid Peroxidation; Location; Luciferases; Malignant Neoplasms; Maps; Measures; Methodology; Modeling; Mouse Strains; Mus; Nature; Nucleic Acid Regulatory Sequences; Oxidative Stress; Phorbol Esters; Population; Predisposition; Prevention strategy; Promoter Regions; Protocols documentation; Publishing; Reporter; Research; Resistance; Role; Sequence Analysis; Severities; Skin; Skin Carcinogenesis; Skin Neoplasms; Staging; Study Section; Susceptibility Gene; Syndrome; System; Testing; Tetradecanoylphorbol Acetate; Transgenic Organisms; Tumor Promotion; Variant; Wild Type Mouse; cDNA Arrays; cancer prevention; carcinogenesis; congenic; glutathione S-transferase alpha; interest; keratinocyte; novel; promoter; response; trait; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The primary goal of the research proposed in this grant application is to identify and characterize genes that modify susceptibility to skin tumor promotion using the multi-stage skin carcinogenesis model in mice. Much data from both human epidemiologic and animal studies support the hypothesis that cancer susceptibility in the general population is a function of multiple, poorly penetrant modifier genes that control the propensity toward environmental carcinogen-induced tumor development. Data suggest that susceptibility to the tumor promotion stage is a major determinant of overall susceptibility to multi-stage, epidermal carcinogenesis in mice. Identifying and characterizing genes that modify susceptibility to tumor promotion is crucial for a complete understanding of multistage carcinogenesis and for developing effective cancer prevention strategies. Genes that modify susceptibility and severity of other disease syndromes in humans have successfully been identified in animal models using approaches similar to those proposed in this application to identify and characterize promotion susceptibility loci. To identify genes that modify promotion susceptibility, we have used the classic multi-stage skin tumorigenesis model in the mouse, which is an excellent animal model to study epithelial carcinogenesis in humans. Genetic control of susceptibility to skin tumor promotion by the phorbol ester, 12- O-tetradecanoylphorbol-13-acetate (TPA), in crosses between susceptible DBA/2 and resistant C57BL/6 mice is a multigenic trait and we have mapped promotion susceptibility loci to chromosomes (chr) 1 (Psl3), 2 (Psl2), 9 (Psl1), and 19 (Psl4). Analysis of C57BL/6.Psl1dba congenic mouse strains suggests that at least three genes underlie the effects of Psl1 on skin tumor promotion susceptibility. We have designated these loci as Psl1.1, Psl1.2, and Psl1.3. Furthermore, global gene expression analyses using cDNA microarrays revealed that glutathione S-transferase alpha 4 (Gsta4), which maps within Psl1.2, is expressed at 20-fold higher levels in the epidermis of TPA-treated C57BL/6 compared to DBA/2 mice. Gsta4 is a glutathione-S-transferase (GST) and a major substrate for Gsta4 is 4-hydroxy-2(E)-nonenal (4-HNE), a product of lipid peroxidation. Recent preliminary studies indicate that C57BL/6 mice, null for Gsta4, are more sensitive than wild-type mice to the multi-stage skin tumor protocol, using TPA as a promoter. These observations, taken together with published data supporting a role for Gsta4 in response to oxidative stress, suggests that Gsta4 is a good candidate for a gene that underlies the effect of Psl1.2 on TPA promotion susceptibility. In the proposed research, we will test the hypotheses that Gsta4 modifies the response to TPA skin tumor promotion in DBA/2 and C57BL/6 mice by regulating the level of 4-HNE following TPA treatment. We will further characterize the Psl1.2 locus to determine if any other genes mapping within the locus are modifiers of TPA skin tumor promotion susceptibility. In addition, we will identify and characterize genes mapping to Psl1.1 and Psl1.3 that are associated with responsiveness to TPA-induced skin tumor promotion in DBA/2 and C57BL/6 mice. The Specific Aims are: i) To further characterize the role of Gsta4 as a modifier of TPA skin tumor promotion susceptibility; ii) To characterize the mechanism for, and consequences of, strain-specific induction of Gsta4; and iii) To identify and characterize genes mapping within the Psl1.1 and Psl1.3 loci that modify the response to TPA skin tumor promotion. PUBLIC HEALTH RELEVANCE: The primary goal of the research proposed in this grant application is to identify and characterize genes that modify susceptibility to skin tumor promotion using the multi- stage skin carcinogenesis model in mice. Data generated from these studies will lead to identification of genes that regulate susceptibility to cancer in human populations and the development of novel cancer prevention strategies.

描述（由申请人提供）：本赠款申请中提出的研究的主要目标是识别和表征基因，这些基因使用小鼠中多阶段的皮肤致癌模型来改变对皮肤肿瘤促进的敏感性。人类流行病学和动物研究的许多数据都支持以下假设：普通人群中的癌症易感性是多种，渗透性良好的修饰剂基因的函数，这些基因控制着环境致癌物诱导的肿瘤发展的倾向。数据表明，对肿瘤促进阶段的敏感性是对小鼠多阶段表皮致癌的总体敏感性的主要决定因素。识别和表征改变肿瘤促进易感性的基因对于完全了解多阶段癌变和制定有效的癌症预防策略至关重要。在动物模型中成功鉴定了与本应用程序中提出的方法相似的方法，在动物模型中成功鉴定了其他疾病综合症的敏感性和严重程度的基因，以识别和表征促进敏感性基因座。为了鉴定改变促进敏感性的基因，我们使用了小鼠中经典的多阶段皮肤肿瘤发生模型，这是研究人类中上皮癌发生的一种极好的动物模型。 Genetic control of susceptibility to skin tumor promotion by the phorbol ester, 12- O-tetradecanoylphorbol-13-acetate (TPA), in crosses between susceptible DBA/2 and resistant C57BL/6 mice is a multigenic trait and we have mapped promotion susceptibility loci to chromosomes (chr) 1 (Psl3), 2 (Psl2), 9 (Psl1),和19（psl4）。 C57BL/6.PSL1DBA的Encynic小鼠菌株的分析表明，至少三个基因是PSL1对皮肤肿瘤促进易感性的影响。我们将这些基因座指定为PSL1.1，PSL1.2和PSL1.3。此外，使用cDNA微阵列进行了全球基因表达分析，显示与DBA/2小鼠相比，在TPA处理的C57BL/6的表皮中，谷胱甘肽S-转移酶Alpha 4（GSTA4）在PSL1.2中绘制的映射在PSL1.2中，在20倍以上。 GSTA4是谷胱甘肽-S-转移酶（GST），GSTA4的主要底物是4-羟基-2（E） - 非烯酸（4-HNE），这是脂质过氧化的产物。最近的初步研究表明，使用TPA作为启动子，C57BL/6小鼠（GSTA4无效）对多阶段的皮肤肿瘤方案比野生型小鼠更敏感。这些观察结果与已发表的数据一起支持GSTA4响应氧化应激的作用，这表明GSTA4是基因的良好候选者，该基因是PSL1.2对TPA促进易感性的影响的基础。在拟议的研究中，我们将通过调节TPA治疗后的4-HNE水平来测试GSTA4对DBA/2和C57BL/6小鼠中对TPA皮肤肿瘤促进的反应的假设。我们将进一步表征PSL1.2基因座，以确定该基因座中的任何其他基因映射是否是TPA皮肤肿瘤促进易感性的修饰符。此外，我们将识别并表征映射到PSL1.1和PSL1.3的基因，这些基因与对TPA诱导的DBA/2和C57BL/6小鼠的皮肤肿瘤促进的反应有关。具体目的是：i）进一步表征GSTA4作为TPA皮肤肿瘤促进敏感性的修饰符的作用； ii）表征GSTA4应变特异性诱导的机制和后果； iii）识别和表征psl1.1和psl1.3基因座中映射的基因，以改变对TPA皮肤肿瘤促进的反应。公共卫生相关性：本赠款应用中提出的研究的主要目标是识别和表征使用小鼠中多阶段皮肤致癌模型来改变对皮肤肿瘤促进的敏感性的基因。这些研究产生的数据将导致鉴定基因，这些基因调节人群中对癌症的易感性以及新型癌症预防策略的发展。