ODC-Az as a Tumor Suppressor by DNA Demethylation

ODC-Az 通过 DNA 去甲基化作为肿瘤抑制剂

• 批准号: 6722776
• 负责人: TAKANORI TSUJI
• 金额: $ 24.1万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722776
• 关键词: DNA methylation; apoptosis; athymic mouse; carcinogenesis; cell growth regulation; chimeric proteins; computer data analysis; enzyme activity; enzyme inhibitors; gene expression; gene induction /repression; genetic manipulation; genetically modified animals; head /neck neoplasm; human tissue; metastasis; microarray technology; nucleic acid probes; ornithine decarboxylase; polymerase chain reaction; regulatory gene; squamous cell carcinoma; tumor suppressor genes

DESCRIPTION (provided by applicant): This is a four-year proposal to examine novel anti-tumor activities of ornithine decarboxylase-antizyme (ODC-Az) in carcinogenesis by a DNA demethylation mechanism. ODC-Az is an intracellular inhibitory molecule of ornithine decarboxylase (ODC) enzyme activity that causes polyamine depletion, which is, implicated in anti-proliferation and differentiation. Expression of ODC-Az is, significantly reduced in animal and human oral cancer cells compared with normal counterparts. Forced-expression of the ODC-Az gene in oral cancer cells altered malignant phenotype by re-activation of genes involved in tumor suppression. Several genes up regulated by ODC-Az are known to be silenced in tumor cells owing to aberrant hypermethylation of the promoter region. Based on this evidence, this application proposes experiments to test the following hypotheses; 1) ODC-Az re-activates tumor suppression-related genes silenced in tumor cells by DNA aberrant hypermethylation, 2) ODC-Az is a potential physiological tumor suppressor molecule. This proposal is design to utilize newly developed strategies, such as cDNA arrays, genetically engineered animal of cancer models and protein transduction systems. This is a novel and promising pathway to counter the deregulated growth and differentiation as well as the silencing mechanism of tumor suppressor genes in cancer cells. The mechanism, by which the regulatory genes involved in normal function of growth invasion and metastasis may become affected by DNA methylation, will be, investigated in the proposed studies. There are two Specific Aims in this proposal: 1) To elucidate the gene expression profile regulated by ODC-Az in human head and neck cancer and 2) To validate ODC-Az as a physiological tumor suppressor molecule. The long-term goal of this project is to determine if ODC-Az could be use therapeutically as a physiological growth suppressor, inducer of terminal differentiation, and inducer of DNA demethylation for reactivation of tumor suppressor genes in the treatment of patients with cancer.

描述（由申请人提供）：这是一个四年的建议，旨在检查通过DNA脱甲基化机制在致癌作用中鸟氨酸脱羧酶 - 抗抗糖酶（ODC-AZ）的新型抗肿瘤活性。 ODC-AZ是鸟氨酸脱羧酶（ODC）酶活性的细胞内抑制性分子，会导致多胺消耗，这与抗增殖和分化有关。 与正常同行相比，动物和人口腔癌细胞的ODC-AZ表达显着降低。 ODC-AZ基因在口腔癌细胞中的强制表达通过重新激活参与肿瘤抑制的基因来改变恶性表型。 由于启动子区域的异常高甲基化，已知在ODC-AZ调节的几个基因被认为在肿瘤细胞中被沉默。 基于此证据，该申请提出了测试以下假设的实验。 1）ODC-AZ通过DNA异常高甲基化，2）ODC-AZ是一种潜在的生理肿瘤抑制分子。 该建议是设计新开发的策略，例如cDNA阵列，癌症模型和蛋白质转导系统的基因工程动物。 这是一种应对癌细胞中肿瘤抑制基因的沉默机制的新型且有希望的途径。 在拟议的研究中，将研究参与生长侵袭和转移正常功能的调节基因可能会受到DNA甲基化的影响的机制。 该提案中有两个具体的目的：1）阐明由ODC-AZ在人头和颈部癌中调节的基因表达谱以及2）验证ODC-AZ作为生理肿瘤抑制分子。该项目的长期目标是确定ODC-AZ是否可以在治疗中用作生理生长抑制剂，终末分化的诱导剂，以及DNA脱甲基化诱导剂在癌症患者治疗中重新激活肿瘤抑制基因。