Roles of NADPH Oxidase 5 and Dual Oxidase 2 in Cancer

NADPH 氧化酶 5 和双氧化酶 2 在癌症中的作用

• 批准号: 8763336
• 负责人: James Doroshow
• 金额: $ 60.66万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8763336
• 关键词: Binding; Biological Models; Bystander Effect; Calcium; Cell Cycle Progression; Cell Proliferation; Cell model; Evaluation; Exposure to; Family member; Genes; Goals; Human; Hydrogen Peroxide; In Vitro; Interferon Type II; Ionomycin; Laboratories; Lead; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mediating; Metabolism; NADPH Oxidase; Normal tissue morphology; Oxidants; Oxidases; Oxygen; Play; Proteins; Role; Signal Transduction; Therapeutic Intervention; carcinogenesis; extracellular; gastrointestinal; melanoma; neoplastic cell; overexpression; pancreatic neoplasm; promoter; tumor

Our laboratory has completed one of the first comprehensive evaluations of the presence of NADPH oxidase family members in human tumors. We found that NADPH oxidase 5 (NOX 5)is found in melanomas and in hematologic malingancies; dual oxidase 2 is found in various gastrointestinal malignancies. We have either over-exposed or upregulated the expression of both of these human proteins in melanoma and pancreatic tumor cell model systems to understand their functions in vitro. NOX 5 overexpression has been found to downregulate p27, alter cell cycle progression, and generate considerable amounts of extracellular hydrogen peroxide after exposure to ionomycin. Duox 2 overexpression has been found to also lead to a remarkable degree of extracellular reactive oxygen metabolism, to be inducible with interferon gamma which functions, in part, by enhancing stat 1 binding to the duox 2 promoter. Both of these genes may play an important role in producing an oxidant "bystander" effect. Our overall goal is to understand the function of these oxidases in human cancer, which, to date has not been explored in detail.

我们的实验室已经完成了人类肿瘤中NADPH氧化酶家族成员存在的第一个全面评估之一。我们发现NADPH氧化酶5 （NOX 5）存在于黑色素瘤和血液病中；双氧化酶2存在于多种胃肠道恶性肿瘤中。我们在黑色素瘤和胰腺肿瘤细胞模型系统中过度暴露或上调这两种人类蛋白的表达，以了解它们在体外的功能。研究发现，NOX 5过表达可下调p27，改变细胞周期进程，并在暴露于离子霉素后产生相当数量的细胞外过氧化氢。Duox - 2过表达也会导致显著程度的细胞外活性氧代谢，这是由干扰素诱导的，其部分功能是通过增强stat1与Duox - 2启动子的结合。这两种基因可能在产生氧化“旁观者”效应中起重要作用。我们的总体目标是了解这些氧化酶在人类癌症中的功能，迄今为止还没有详细探索过。