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: 6870275
• 负责人: TAKANORI TSUJI
• 金额: $ 24.15万
• 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/6870275
• 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）：这是一项为期四年的提案，旨在通过 DNA 去甲基化机制研究鸟氨酸脱羧酶抗酶 (ODC-Az) 在致癌作用中的新型抗肿瘤活性。 ODC-Az 是鸟氨酸脱羧酶 (ODC) 酶活性的细胞内抑制分子，可导致多胺消耗，从而参与抗增殖和分化。 与正常细胞相比，动物和人类口腔癌细胞中 ODC-Az 的表达显着降低。 口腔癌细胞中 ODC-Az 基因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。 已知 ODC-Az 上调的几个基因在肿瘤细胞中由于启动子区域的异常高甲基化而被沉默。 基于这一证据，本申请提出了实验来检验以下假设； 1) ODC-Az 重新激活肿瘤细胞中因 DNA 异常高甲基化而沉默的肿瘤抑制相关基因，2) ODC-Az 是一种潜在的生理性肿瘤抑制分子。 该提案旨在利用新开发的策略，例如cDNA阵列、基因工程动物癌症模型和蛋白质转导系统。 这是一种新颖且有前景的途径，可以对抗癌细胞中生长和分化失调以及肿瘤抑制基因的沉默机制。 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受到 DNA 甲基化影响的机制。 该提案有两个具体目标：1) 阐明 ODC-Az 在人类头颈癌中调控的基因表达谱；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 是否可以在癌症患者的治疗中用作生理生长抑制剂、终末分化诱导剂和 DNA 去甲基化诱导剂以重新激活肿瘤抑制基因。