Modeling Prostate Tumorigenesis

前列腺肿瘤发生建模

• 批准号: 7941603
• 负责人: Sarki A. Abdulkadir
• 金额: $ 13.05万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2011-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941603
• 关键词: Alleles; Androgen Receptor; Androgens; Animals; Antioxidants; Apoptosis; Archives; Biological Assay; Cell Cycle; Cell Proliferation; Cells; Chromatin; Cyclin D1; Defect; Detection; Diagnosis; Dysplasia; Enzymes; Epithelial; Epithelial Cells; Gene Dosage; Gene Expression; Gene Mutation; Gene Targeting; Genes; Hexokinase 2; Histone Acetylation; Human; Hyperplasia; In Vitro; Individual; Inflammation; Inherited; Kinetics; LacZ Genes; Lead; Lectin; Light; Luciferases; Malignant neoplasm of prostate; Modeling; Molecular Profiling; Molecular Target; Mus; Mutant Strains Mice; Mutation; Null Lymphocytes; Pattern; Pre-Clinical Model; Prevention; Process; Prostate; Prostatic; Prostatic Intraepithelial Neoplasias; Prostatic Neoplasms; Proteins; Regulation; Reporter; Role; Sampling; Signal Transduction; System; TP53 gene; Testing; Tissue Sample; Transcriptional Regulation; Tumor Suppression; Tumor Suppressor Genes; Tumorigenicity; angiogenesis; base; chromatin immunoprecipitation; chromatin remodeling; dosage; falls; gene function; genome-wide; glutathione peroxidase; homeodomain; in vivo; insight; mathematical model; mutant; overexpression; oxidative DNA damage; oxidative damage; peroxiredoxin; programs; promoter; protein expression; research study; response; sulfhydryl oxidase; transcription factor; tumor initiation; tumorigenesis

PROJECT SUMMARY Studies of human and mouse prostate cancer indicate that the homeodomain-containing transcription factor Nkx3.1 is an important haplo-insufficient tumor suppressor gene involved in prostate tumor initiation. Nkx3.1 protein expression is lost in human and mouse prostate tumors, and a recent study has found Nkx3.1 mutations in hereditary prostate cancer. We have generated and characterized conventional and conditional Nkx3.1 mutant mice. These mice develop prostatic epithelial hyperplasia and dysplasia and have been extensively studied as a model of prostatic intraepithelial neoplasia (PIN). In these animals, the exit of differentiating prostate luminal epithelial cells from the cell cycle is delayed, resulting in prostatic epithelial hyperplasia and subsequently PIN. Further analysis of Nkx3.1 mutant mice has revealed several features that begin to shed light on the mechanisms of tumor suppression by this protein. Nkx3.1 regulates a class of genes in a dosage-sensitive and stochastic manner, a phenomenon that may underlie haplo-insufficiency and which appears to be dictated by the differential chromatin states of target genes. Nkx3.1 regulates the expression of cell cycle regulators as well as a unique class of androgen target genes. Further, loss of Nkx3.1 dysregulates the expression of pro- and anti-oxidant enzymes (including peroxiredoxin 6, glutathione peroxidase 3 and sulfhydryl oxidase 6) resulting in loss of protection against oxidative damage. It is our hypothesis that loss of Nkx3.1 promotes prostate tumor initiation by deregulating multiple gene programs that alter cell cycle exit, androgen signaling, and the anti-oxidant response. We have outlined specific experi- ments to test this hypothesis according to the following aims: 1) To examine the regulation and function of dosage-sensitive Nkx3.1 target genes. 2) To define the regulation and function of genes induced by androgen specifically in Nkx3.1-deficient cells. 3) To test the notion that disruption of the anti-oxidant defense system in Nkx3.1 mutant mice leads to the accumulation of genetic mutations. PROJECT NARRATIVE The significance of these studies lies in their potential to increase our understanding of the mechanisms of prostate tumor initiation and to generate molecular targets for diagnosis and prevention in a preclinical model.

项目摘要 人类和小鼠前列腺癌的研究表明，含同源域的转录 因子NKX3.1是参与前列腺肿瘤起始的重要单倍抑制基因。 NKX3.1蛋白表达在人和小鼠前列腺肿瘤中丧失，最近的一项研究发现了NKX3.1 遗传前列腺癌的突变。我们已经生成并表征了常规和条件 NKX3.1突变小鼠。这些小鼠会出现前列腺上皮增生和发育不良，一直存在 广泛研究了前列腺上皮内肿瘤（PIN）的模型。在这些动物中，出口 将前列腺腔上皮细胞与细胞周期区分开，导致前列腺上皮 增生和随后的销钉。 NKX3.1突变小鼠的进一步分析揭示了几个功能 开始阐明该蛋白质抑制肿瘤的机制。 NKX3.1调节 以剂量敏感和随机方式的基因，这种现象可能是单倍不高兴的基础 这似乎由靶基因的差异染色质状态决定。 NKX3.1调节 细胞周期调节剂的表达以及独特的雄激素靶基因。此外，NKX3.1的损失 促氧化酶的表达不足（包括过氧蛋白6，谷胱甘肽 过氧化物酶3和硫酰氧化酶6）导致无法防止氧化损伤的保护。这是我们的 假设NKX3.1的丧失通过放松多个基因程序来促进前列腺肿瘤的启动 改变细胞周期出口，雄激素信号传导和抗氧化剂反应。我们概述了特定的经验 根据以下目的检验该假设的方法：1）检查的调节和功能 剂量敏感的NKX3.1靶基因。 2）定义由雄激素诱导的基因的调节和功能 特别是在NKX3.1缺陷型细胞中。 3）测试抗氧化防御系统中断的观念 NKX3.1突变小鼠导致遗传突变的积累。项目叙述 这些研究的意义在于它们的潜力增加了我们对机制的理解 前列腺肿瘤的启动并产生用于临床前诊断和预防的分子靶标 模型。