Analysis of arsenic in inducing ROS, signaling pathways, and lung carcinogenesis

砷诱导ROS、信号通路和肺癌发生的分析

• 批准号: 8130216
• 负责人: BingHua Jiang
• 金额: $ 23.2万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8130216
• 关键词: Affect; Air; Arsenic; Binding; Biological; Bronchiectasis; Carcinogens; Cells; Environment; Epidemiologic Studies; Epithelial Cells; Etiology; Exposure to; Future; Generations; Human; Intervention; Learning; Link; Liver; Lung; Lung diseases; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Membrane; Minerals; Molecular; NADPH Oxidase; Non-Malignant; Production; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skin; Smoke; Soil; Testing; Transcriptional Activation; Vascular Diseases; Vascular Endothelial Growth Factors; Water; angiogenesis; base; carcinogenesis; cell transformation; lung carcinogenesis; prevent; public health relevance; tumor growth; tumorigenesis

DESCRIPTION (provided by applicant): Arsenic is widely spread in the environment such as soil, minerals, smoke, contaminated air and water. Epidemiologic studies showed that inorganic arsenic exposure induced lung, skin, liver, and bladder cancers. However, the etiology and molecular mechanisms of arsenic in inducing carcinogenesis still remain to be elucidated. Arsenic is also strongly linked to non-malignant lung vascular diseases. Our preliminary results showed that exposure of lung epithelial cells to arsenic produced high levels of reactive oxygen species (ROS). Arsenic induced AKT and ERK1/2 activation, and increased HIF-1 expression and VEGF transcriptional activation. We hypothesize that arsenic induces carcinogenesis through ROS signaling, which in turn regulates PI3K, AKT, ERK1/2, and HIF-1. To test this hypothesis, we will perform the following two aims. In Aim 1, we will identify which species of ROS induced by arsenic and the mechanism of ROS generation in the lung epithelial cells, then determine whether arsenic regulates PI3K, AKT, and ERK activation through ROS generation in the cells. Aim 2 will determine the role of arsenic in inducing tumorigenesis, and whether arsenic induces tumorigenesis through ROS production, PI3K, AKT, ERK1/2, and HIF-1 expression. We will study signaling pathways and molecules that regulate the progression of arsenic-inducing tumor growth. After we learn the effects and the underlying mechanism of arsenic in inducing carcinogenesis, we will be able to develop mechanism-based interventions to prevent carcinogenesis induced by arsenic in the future. PUBLIC HEALTH RELEVANCE: Arsenic is widely spread in the environment such as soil, minerals, smoke, contaminated air and water. Arsenic is known carcinogen for inducing human cancer. However, the etiology and molecular mechanisms of arsenic in inducing carcinogenesis still remain to be elucidated. In this study, we plan to study the roles and mechanism of arsenic in inducing signaling pathways and molecules that are associated with carcinogenesis and tumorigenesis, and to analyze these signaling molecules in arsenic-inducing tumorigenesis. This information will be useful for us to develop mechanism-based interventions to prevent arsenic-inducing carcinogenesis in the future.

描述（申请人提供）：砷广泛分布于土壤、矿物质、烟雾、受污染的空气和水等环境中。流行病学研究表明，接触无机砷会诱发肺癌、皮肤癌、肝癌和膀胱癌。然而，砷致癌的病因和分子机制仍有待阐明。砷还与非恶性肺血管疾病密切相关。我们的初步结果表明，肺上皮细胞暴露于砷会产生高水平的活性氧（ROS）。砷诱导 AKT 和 ERK1/2 激活，并增加 HIF-1 表达和 VEGF 转录激活。我们假设砷通过 ROS 信号传导诱导癌变，进而调节 PI3K、AKT、ERK1/2 和 HIF-1。为了检验这个假设，我们将实现以下两个目标。在目标1中，我们将鉴定砷诱导的ROS种类以及肺上皮细胞中ROS生成的机制，然后确定砷是否通过细胞中ROS生成来调节PI3K、AKT和ERK活化。目标 2 将确定砷在诱导肿瘤发生中的作用，以及砷是否通过 ROS 产生、PI3K、AKT、ERK1/2 和 HIF-1 表达诱导肿瘤发生。我们将研究调节砷诱导肿瘤生长进程的信号通路和分子。当我们了解砷致癌的作用和潜在机制后，我们将来将能够开发基于机制的干预措施来预防砷致癌。公众健康相关性：砷广泛分布于土壤、矿物质、烟雾、受污染的空气和水等环境中。砷是已知的致癌物质，可诱发人类癌症。然而，砷致癌的病因学和分子机制仍有待阐明。在本研究中，我们计划研究砷在诱导与癌变和肿瘤发生相关的信号通路和分子中的作用和机制，并分析这些信号分子在砷诱导肿瘤发生中的作用。这些信息将有助于我们开发基于机制的干预措施，以预防未来砷诱发的致癌作用。