Mechanisms of As-Induced Carcinogenesis

描述(申请人提供)：砷仍然是美国和世界范围内最受关注的环境问题，因为它在全球范围内存在，并对健康造成严重影响。流行病学研究提供了充分的证据表明，接触亚砷酸盐与皮肤癌和肺癌发病率的增加有关。父母资助的范围涉及人体角质形成细胞和小鼠皮肤模型中由于亚砷酸盐暴露而产生的活性氧(ROS)与皮肤癌的关系。虽然目前的竞争性修订范围试图评估在体外和体内将亚砷酸盐诱导的慢性炎症与肺癌发生联系起来的贡献和分子机制，但这一竞争性修订试图扩大最初的研究范围，从介导皮肤癌变的ROS产生，扩展到在体外和体内细胞和动物对亚砷酸盐暴露的反应中将亚砷酸盐诱导的慢性炎症与肺肿瘤发生联系的分子机制的鉴定。尽管母基金和目前的竞争性修订都建议研究亚砷酸盐暴露致癌作用的机制，但这次修订的目的是明确关键的炎症介质肿瘤坏死因子-1和环氧合酶-2在亚砷酸盐诱导的人支气管上皮细胞(HBECs)体外和体内致瘤性发展中的作用，以及参与这一致癌过程的分子机制。这一修订的主要假设是，肿瘤坏死因子-1在持续慢性肺部炎症的形成和维持中发挥核心作用，并随后导致砷暴露导致肺上皮细胞肿瘤的发生。本研究的总体目标是确定肿瘤坏死因子-1和环氧合酶-2在亚砷酸盐诱导的血管内皮细胞致瘤性中的作用，以及在体内和体外砷暴露过程中肿瘤坏死因子-1在维持肺慢性炎症中的核心作用。本研究有两个具体目的：1)确定肿瘤坏死因子-1和环氧合酶-2在砷暴露所致的血管内皮细胞致瘤性中的作用；2)探讨肿瘤坏死因子-1在砷诱导的肺慢性炎症中的中心作用及其体内机制。此次修订的成功将有助于我们理解慢性肺炎性微环境的形成和维持的分子机制(S)，以及它在砷暴露诱发肺癌发生中的作用。更好地了解这些问题可能会为设计更有效的预防和治疗炎症相关肺癌的药物提供宝贵的信息。此外，这一竞争性修订的资金将节省两个工作，一个是余建秀博士的兼职工作，另一个是张冬云博士的工作，这两个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。由于我们拥有大多数研究工具，研究动物可以在我们的实验室或商业上获得，我们相信拟议的研究将在两年内实现。 与公共健康相关：砷仍然是美国和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亚砷酸盐暴露导致肺癌发生的主要驱动力，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完全不清楚。这一应用是为了验证这一假说，即肿瘤坏死因子-1在砷暴露所致的持续慢性肺部炎症的形成和维持以及诱导肺上皮细胞肿瘤的发生中起核心作用。此次修订的成功将有助于我们理解慢性炎症微环境的形成和维持的分子机制(S)，以及它在砷暴露诱发肺癌发生中的作用。更好地了解这些问题可能为设计更有效的预防和治疗炎症相关肺癌的药物提供必要的有价值的信息。

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.