Molecular Mechanisms of Nickel-induced Tumorigenicity.

镍诱导致瘤性的分子机制。

• 批准号: 8601807
• 负责人: CHUANSHU HUANG
• 金额: $ 27.15万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8601807
• 关键词: Abbreviations; Alkaline Phosphatase; Anti-Inflammatory Agents; Anti-inflammatory; Calcineurin; Cells; Chronic; Complement Factor B; Cyclosporine; Development; EMSA; Electrophoresis; Electrophoretic Mobility Shift Assay; Embryo; Environment; Epidemiologic Studies; Epithelial Cells; Exposure to; Feedback; Fibroblasts; Funding; Glycogen Synthase Kinase 3; Goals; Human; Immunoglobulin G; In Vitro; Inflammation; Inflammatory; International Agency for Research on Cancer; Laboratories; Lead; Link; Lung; Lung Inflammation; Maintenance; Malignant neoplasm of lung; Manganese Superoxide Dismutase; Mediating; Mediation; Mitochondria; Molecular; Mus; Nickel; Non-Small-Cell Lung Carcinoma; Non-Steroidal Anti-Inflammatory Agents; Nuclear; Outcome; PTGS2 gene; Pathway interactions; Pharmaceutical Preparations; Phosphotransferases; Polymerase Chain Reaction; Prevention therapy; Process; Progress Reports; Publications; Reactive Oxygen Species; Resources; Reverse Transcriptase Polymerase Chain Reaction; Reverse Transcription; Role; Small Interfering RNA; Superoxide Dismutase; TNF gene; Testing; Tetradecanoylphorbol Acetate; Training; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Tumorigenicity; Vascular Endothelial Growth Factors; airway inflammation; base; carcinogenesis; catalase; chromatin immunoprecipitation; cyclooxygenase 2; design; driving force; fetal bovine serum; in vivo; inhibitor/antagonist; lung carcinogenesis; lung small cell carcinoma; novel; nuclear factors of activated T-cells; overexpression; public health relevance; response; success; tool; ultraviolet

DESCRIPTION (provided by applicant): This competitive renewal application will continue examining the molecular mechanisms by which nickel compounds mediate lung carcinogenesis. In particular, this proposal seeks to identify the molecular mechanisms linking nickel-induced lung sustained inflammation to tumorigenicity of human bronchial epithelial cells (HBECs) in vitro and in vivo. Although there is an association between nickel- induced sustained airway inflammation and lung cancer development, the molecular mechanisms linking nickel exposure to the sustained lung chronic inflammation are not understood yet. The studies obtained from the last funding period and preliminary studies demonstrate that nickel exposure results in the activation of the nuclear factor-:B (NF:B), which in turn mediates COX-2 induction. Our studies also show that nickel exposure enables activation of AP-1, which in turn mediates TNF-1 induction. Furthermore, we find that TNF-1 enables COX-2 induction through the NFAT-dependent pathway. In addition, we find that there is crosstalk between the NFAT and NF?B pathways during cellular response to nickel exposure. Thus, the main hypothesis of this renewal proposal is that the NFAT/ NF?B activation and the pro-inflammatory TNF-1 and COX-2 induction will form positive inflammatory feedback loops, which are responsible for the formation and maintenance of sustained chronic lung inflammation and the induction of lung epithelial cell tumorigenicity due to nickel exposure. We propose the following Specific Aims: 1), To test the hypothesis that the inflammatory positive feedback loops being formed by NF?B, NFAT, and TNF1 are responsible for the maintenance of sustained COX-2 induction due to nickel exposure in HBECs; 2), To determine the role of the positive inflammatory feedback loops in the development of tumorigenicity induced by nickel exposure in HBECs.; 3), To assess the central role of TNF-1 in nickel-induced chronic lung inflammation and its mechanisms in vivo. The overall goal of this proposal is to clarify the formation of positive inflammatory feedback loops among NFAT, NF?B, TNF-1 and COX-2, in nickel exposure both in vitro and in vivo, and to determine the role of the positive inflammatory feedback loops in nickel-induced HBECs' tumorigenicity, as well as the central role of TNF-1 in the maintenance of lung sustained chronic inflammation and lung carcinogenesis during nickel exposure in vivo. Success of the proposal will facilitate our understanding of the molecular mechanism(s) that lead to the formation and maintenance of a lung chronic inflammatory microenvironment, and its role in lung carcinogenesis due to nickel exposure. A better understanding of these issues may provide valuable information for the designing of more effective agents for the prevention and therapy of lung cancers. We believe that the proposed contribution of positive inflammatory feedback loop responsible for nickel-induced lung tumorigenicity is novel.

描述(由申请人提供)：这项竞争性更新申请将继续研究镍化合物介导肺癌发生的分子机制。特别是，这项建议试图确定镍诱导的肺持续炎症与体内和体外人支气管上皮细胞(HBECs)致瘤性之间的分子机制。尽管镍诱导的持续性呼吸道炎症与肺癌的发生有关，但镍暴露与持续性肺部慢性炎症之间的分子机制尚不清楚。上一次资助期的研究和初步研究表明，镍暴露导致核因子-B(NF：B)的激活，而核因子-B又介导了COX-2的诱导。我们的研究还表明，镍暴露能够激活AP-1，而AP-1又介导了肿瘤坏死因子-1的诱导。此外，我们还发现，肿瘤坏死因子-1通过NFAT依赖的途径诱导COX-2的表达。此外，我们还发现，在细胞对镍暴露的反应过程中，NFAT和NF？B通路之间存在串扰。因此，这一更新建议的主要假设是，NFAT/NF？B的激活和促炎性肿瘤坏死因子-1和环氧合酶-2的诱导将形成正的炎症反馈环，这些环负责持续慢性肺部炎症的形成和维持，并诱导镍暴露所致的肺上皮细胞肿瘤形成。我们提出的具体目标如下：1)验证由NF？B、NFAT和TNF1形成的炎性正反馈环负责维持镍暴露所致HBECs持续的COX-2诱导的假说；2)确定炎性正反馈环在镍诱导的HBECs致瘤性发展中的作用；3)评估肿瘤坏死因子-1在镍诱导的慢性肺炎症中的中心作用及其体内机制。本研究的总体目标是阐明体内和体外镍暴露中NFAT、核因子？B、肿瘤坏死因子-1和环氧合酶-2之间的正向炎症反馈环的形成，确定正向炎症反馈环在镍诱导的血管内皮细胞致瘤性中的作用，以及肿瘤坏死因子-1在体内镍暴露中维持肺持续慢性炎症和肺癌发生中的核心作用。该方案的成功将有助于我们理解导致肺慢性炎症微环境形成和维持的分子机制(S)，以及它在镍暴露所致肺癌发生中的作用。更好地了解这些问题可能为设计更有效的肺癌预防和治疗药物提供有价值的信息。我们认为，正向炎症反馈环在镍诱导的肺肿瘤发生中的作用是新的。