Modeling Prostate Tumorigenesis

前列腺肿瘤发生建模

基本信息

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
项目类别：
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

项目摘要

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.

项目概要对人和小鼠前列腺癌的研究表明，含有同源结构域的转录 Nkx3.1 因子是参与前列腺肿瘤发生的重要单倍体不足抑癌基因。 Nkx3.1蛋白表达在人类和小鼠前列腺肿瘤中丢失，最近的一项研究发现Nkx3.1 遗传性前列腺癌的突变。我们已经生成并表征了常规和条件 Nkx3.1突变小鼠。这些小鼠出现前列腺上皮增生和发育不良，并已被作为前列腺上皮内瘤变（PIN）的模型进行了广泛研究。在这些动物中，前列腺管腔上皮细胞从细胞周期的分化被延迟，导致前列腺上皮细胞增生和随后的 PIN。对 Nkx3.1 突变小鼠的进一步分析揭示了以下几个特征：开始揭示这种蛋白质抑制肿瘤的机制。 NKx3.1调节一类基因以剂量敏感和随机的方式，这种现象可能是单倍体不足和这似乎是由靶基因的差异染色质状态决定的。 Nkx3.1 调节细胞周期调节因子以及一类独特的雄激素靶基因的表达。此外，Nkx3.1 的丢失失调促氧化酶和抗氧化酶（包括过氧化还原蛋白 6、谷胱甘肽过氧化物酶 3 和巯基氧化酶 6) 导致失去针对氧化损伤的保护。这是我们的假设 Nkx3.1 的缺失通过解除对多个基因程序的管制来促进前列腺肿瘤的发生改变细胞周期退出、雄激素信号传导和抗氧化反应。我们概述了具体的经验根据以下目标来检验这一假设： 1）检验剂量敏感的 Nkx3.1 靶基因。 2) 明确雄激素诱导基因的调控和功能特别是在 Nkx3.1 缺陷细胞中。 3) 检验抗氧化防御系统被破坏的观点 Nkx3.1突变小鼠导致基因突变积累。项目叙述这些研究的意义在于它们有可能增加我们对机制的理解前列腺肿瘤的发生并产生临床前诊断和预防的分子靶点模型。