Mechanisms of As-Induced Carcinogenesis

砷诱发的致癌机制

• 批准号: 7844264
• 负责人: CHUANSHU HUANG
• 金额: $ 66.35万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844264
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Address; Alkaline Phosphatase; Animal Experimentation; Animals; Arsenic; Arsenites; Cell Line; Cells; Chronic; Cyclic AMP-Dependent Protein Kinases; Cytomegalovirus; Data; Development; EGF gene; Electron Spin Resonance Spectroscopy; Embryo; Epidemiologic Studies; Epidermal Growth Factor; Epithelial Cells; Exposure to; Feedback; Fibroblasts; Figs - dietary; Funding; Generations; Glycogen Synthase Kinase 3; Goals; Grant; Health; Human; Immunoglobulin G; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; International Agency for Research on Cancer; Investigation; Laboratories; Link; Lipids; Lung; Lung Inflammation; MAP Kinase Gene; MAPK8 gene; MEKs; Maintenance; Malignant neoplasm of lung; Mediating; Mediation; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Nuclear; Occupations; PTGS2 gene; Pathway interactions; Phosphatidylinositols; Phosphotransferases; Play; Postdoctoral Fellow; Prevention therapy; Process; Protein Kinase; ROS1 gene; Reactive Oxygen Species; Research; Role; Signal Transduction; Skin; Skin Carcinogenesis; Small Interfering RNA; Superoxide Dismutase; T-Cell Activation; T-Lymphocyte; Testing; Time; Training; Transcription Factor AP-1; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumorigenicity; United States; base; carcinogenesis; cyclooxygenase 2; design; driving force; extracellular; fetal bovine serum; in vivo; inhibitor/antagonist; keratinocyte; lung carcinogenesis; nuclear factors of activated T-cells; parent grant; platelet protein P47; public health relevance; response; stress-activated protein kinase 1; success; tool; tumorigenic

DESCRIPTION (provided by applicant): Arsenic remains a top environmental concern in the United States as well as world-wide because of its global existence and serious health impacts. Epidemiological studies provide ample evidence that arsenite exposure is associated with the increased incidence of skin and lung cancers. The scope of the parent grant addresses the relation of reactive oxygen species (ROS) generation and skin carcinogenesis due to arsenite exposure in both the human keratinocytes and the mouse skin models. While the scope of current competitive revision seeks to evaluate the contribution and molecular mechanisms of linking the arsenite-induced chronic inflammation to lung carcinogenesis both in vitro and in vivo, this competitive revision seeks to expand the original scope of study from ROS generation in the mediation of skin carcinogenesis, to identification of the molecular mechanisms that link arsenite-induced chronic inflammation to lung tumorigenicity in vitro and in vivo in cellular as well as animal response to arsenite exposure. Although both the parent grant and the current competitive revision propose to study the mechanisms implicated in the carcinogenic effects of arsenite exposure, this revision is specifically intended to identify the contribution of key inflammatory mediators TNF-1 and COX-2 to arsenite-induced development of tumorigenicity of human bronchial epithelial cells (HBECs) in vitro and in vivo, as well as the molecular mechanisms involved in this tumorigenic process. The main hypothesis of this revision is that TNF-1 plays a central role in the formation and maintenance of sustained chronic lung inflammation and subsequently results in the induction of lung epithelial cell tumorigenicity due to arsenic exposure. The overall goal of this proposal is to determine role of TNF-1 and COX-2 in arsenite-induced HBECs' tumorigenicity, as well as the central role of TNF-1 in the maintenance of lung chronic inflammation during arsenic exposure both in vitro and in vivo. There are two Specific Aims proposed for this investigation: 1) To determine the contribution of TNF-1 and COX-2 to the development of tumorigenicity of HBECs due to arsenic exposure; 2) To assess the central role of TNF-1 in arsenic-induced lung chronic inflammation and its mechanisms in vivo. Success of the revision will facilitate our understanding of the molecular mechanism(s) of the formation and maintenance of the chronic lung inflammatory microenvironment, and its role in lung cancer development induced by arsenic exposure. A better understanding of those issues may provide valuable information that is needed for the designing more effective agents for the prevention of and therapy for inflammation-associated lung cancers. Furthermore, funding of this competitive revision will save two jobs, one part-time for Dr. Jianxiu Yu and one for Dongyun Zhang, both of whom provide valuable expertise and are crucial for the proposed studies. The finding will also create new training opportunity for two postdoctoral fellows in the proposed research field. Since we have most of research tools, and research animals are either available in our laboratory or commercially, we believe that the proposed studies will be achieved within two years. PUBLIC HEALTH RELEVANCE: Arsenic remains the top environmental concern in United States as well as world wide, and the existence of a sustained lung chronic inflammatory microenvironment is thought to be a major driving force for the development of lung cancers due to arsenite exposure, however, the molecular mechanisms linking arsenite exposure to lung chronic inflammation are totally unknown. This application is to test the hypothesis that TNF-1 plays a central role in the formation and maintenance of sustained chronic lung inflammation and induction of lung epithelial cell tumorigenicity due to arsenic exposure. Success of the revision will facilitate our understanding of the molecular mechanism(s) of the formation and maintenance of the lung chronic inflammatory microenvironment, and its role in lung cancer development induced by arsenic exposure. A better understanding of those issues may provide valuable information needed for designing more effective agents for prevention and therapy of the inflammation-associated lung cancers.

描述（由申请人提供）：由于砷在全球范围内存在并具有严重的健康影响，因此它仍然是美国乃至全世界最重要的环境问题。流行病学研究提供了充分的证据表明亚砷酸盐暴露与皮肤癌和肺癌发病率增加有关。母基金的范围涉及人类角质形成细胞和小鼠皮肤模型中由于亚砷酸盐暴露而导致的活性氧（ROS）生成与皮肤癌发生之间的关系。虽然当前竞争性修订的范围旨在评估亚砷酸盐诱导的慢性炎症与体外和体内肺癌发生之间的关系的贡献和分子机制，但本次竞争性修订旨在扩大ROS生成在介导中的原始研究范围皮肤癌发生的分子机制，确定将亚砷酸盐诱导的慢性炎症与体外和体内细胞以及动物对亚砷酸盐暴露的反应的肺部致瘤性联系起来的分子机制。尽管母基金和当前的竞争性修订均提议研究亚砷酸盐暴露致癌作用所涉及的机制，但本次修订的具体目的是确定关键炎症介质 TNF-1 和 COX-2 对亚砷酸盐诱导的癌症发展的贡献。人支气管上皮细胞（HBEC）在体外和体内的致瘤性，以及该致瘤过程中涉及的分子机制。本次修订的主要假设是，TNF-1 在持续性慢性肺部炎症的形成和维持中发挥着核心作用，并随后导致由于砷暴露而诱导肺上皮细胞致瘤性。该提案的总体目标是确定 TNF-1 和 COX-2 在亚砷酸盐诱导的 HBEC 致瘤性中的作用，以及 TNF-1 在体外和砷暴露期间维持肺部慢性炎症中的核心作用。体内。本研究提出了两个具体目标： 1) 确定 TNF-1 和 COX-2 对砷暴露引起的 HBEC 致瘤性发展的贡献； 2) 评估TNF-1在砷诱导的肺部慢性炎症中的核心作用及其体内机制。修订的成功将有助于我们了解慢性肺部炎症微环境形成和维持的分子机制，及其在砷暴露诱发肺癌发展中的作用。更好地了解这些问题可能会提供有价值的信息，以设计更有效的药物来预防和治疗与炎症相关的肺癌。此外，本次竞争性修订的资助将节省两项工作，一项是余建秀博士的兼职工作，另一项是张冬云的兼职工作，两人都提供了宝贵的专业知识，对拟议的研究至关重要。这一发现还将为拟议研究领域的两名博士后研究员创造新的培训机会。由于我们拥有大部分研究工具，并且研究动物要么在我们的实验室中要么在商业上可用，我们相信拟议的研究将在两年内实现。 公共卫生相关性：砷仍然是美国乃至世界范围内最受关注的环境问题，持续的肺部慢性炎症微环境的存在被认为是由于亚砷酸盐暴露而导致肺癌发展的主要驱动力，然而，将亚砷酸盐暴露与肺部慢性炎症联系起来的分子机制尚不清楚。本申请旨在检验以下假设：TNF-1 在持续慢性肺部炎症的形成和维持以及砷暴露引起的肺上皮细胞致瘤性诱导中发挥核心作用。修订的成功将有助于我们了解肺部慢性炎症微环境形成和维持的分子机制，及其在砷暴露诱发肺癌发展中的作用。更好地了解这些问题可能会为设计更有效的药物来预防和治疗与炎症相关的肺癌提供所需的有价值的信息。