HIF-alphia in Cr(VI) carcinogenesis

HIF-α 在 Cr(VI) 致癌作用中的作用

基本信息

批准号：
8125028
负责人：
Zhuo Zhang
金额：
$ 33.08万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-09 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8125028
关键词：
Anchorage-Independent Growth Blood Vessels Carcinogens Cell Hypoxia Cell Line Cells Development Diffuse Dominant-Negative Mutation Environmental Carcinogens Epithelial Exposure to Female Generations Genetic Transcription Goals Human Hydrogen Peroxide Hydroxyl Radical Hypoxia In Vitro Incidence Inhalation Exposure International Agency for Research on Cancer MAPK14 gene Malignant Neoplasms Malignant neoplasm of lung Mediating Metabolic NADPH Oxidase Neoplasm Metastasis Nose Nude Mice Nutrient Occupational Occupational Groups Oxidative Stress Oxygen Pathway interactions Physiological Processes Play Post-Translational Protein Processing Process Reactive Oxygen Species Regulation Reporting Role Signal Pathway Signal Transduction Small Interfering RNA Solid Neoplasm Source Superoxides System T-Lymphocyte Testing Thymus Gland Translations Vascular Endothelial Growth Factors Writing angiogenesis cancer initiation carcinogenesis carcinogenicity cell transformation chromium hexavalent ion genetic regulatory protein hypoxia inducible factor 1 in vivo insight millimeter mitogen-activated protein kinase p38 new growth overexpression public health relevance tumor tumor growth tumor progression tumorigenesis wasting

项目摘要

DESCRIPTION (provided by applicant): Although the carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo, its mechanism of action remains to be investigated. Our recent studies indicate that Cr(VI) induces HIF-11 activation. MAP kinase p38 and reactive oxygen species (ROS) are involved in this process. HIF-11 is a key regulatory protein for angiogenesis, which is a physiological process involving the growth of new blood vessels from pre-existing vessels. Solid tumors of smaller than 1 to 2 cubic millimeters are not vascularized. To spread, they need to be supplied by blood vessels that bring oxygen and nutrients and remove metabolic wastes. Inhibition of HIF-11 decreases cell transformation capacity in hypoxia and tumor growth in vivo, while overexpression of HIF-11 allows anchorage-independent growth in normoxia and development of more aggressive tumors. Since HIF-11 is important in cancer initiation and progression, it is likely that HIF-11 activation and angiogenesis could be important in Cr(VI)-mediated carcinogenesis. We hypothesize that ROS and HIF-11 activation play an important role in Cr(VI)-induced carcinogenesis. Human bronchial epithelial BEAS-2B cells and athymic female nude mice (3-4 weeks old) deficient in thymus-dependent (T-cell) immunological functions will be used in the present study. Three specific aims are proposed. Aim 1 will investigate the mechanism of Cr(VI)-induced ROS generation and the role of ROS in activation of HIF-11 and angiogenesis in vitro. The regulation of HIF-1 activity could occur at multiple levels: transcription, translation, and post-translational modifications. The questions remain open concerning at what level Cr(VI) induces HIF-11 activation. Aim 2 will answer that question in cell system. Aim 3 will investigate the roles of ROS and HIF-1 signaling in Cr(VI)-induced cell transformation in vitro, tumorigenesis, tumor growth, and metastasis in vivo. We anticipate that Cr(VI) induces angiogenesis via HIF-11 activation through ROS and MAP kinase p38, promoting Cr(VI)-induced cell transformation, tumorigenesis, tumor growth, and metastasis. . PUBLIC HEALTH RELEVANCE: Hexavalent chromium [Cr(VI)] is a known human carcinogen. The carcinogenicity of Cr(VI) has been well documented by studies both in vitro and in vivo. We hypothesize that Cr(VI) induces oxidative stress and activate HIF-1 angiogenesis signalling pathway, leading to cell transformation, tumorigenesis, tumor growth, and metastasis. The goal of this proposal is to test that hypothesis.

描述（由申请人提供）：尽管体外和体内研究已充分证明 Cr(VI) 的致癌性，但其作用机制仍有待研究。我们最近的研究表明 Cr(VI) 会诱导 HIF-11 激活。 MAP 激酶 p38 和活性氧 (ROS) 参与此过程。 HIF-11 是血管生成的关键调节蛋白，血管生成是一种涉及从现有血管生长出新血管的生理过程。小于1至2立方毫米的实体瘤没有血管化。为了传播，它们需要由血管提供氧气和营养物质并清除代谢废物。 HIF-11 的抑制会降低缺氧条件下的细胞转化能力和体内肿瘤生长，而 HIF-11 的过度表达则允许常氧条件下的贴壁依赖性生长和更具侵袭性的肿瘤的发展。由于 HIF-11 在癌症发生和进展中很重要，因此 HIF-11 激活和血管生成可能在 Cr(VI) 介导的癌发生中发挥重要作用。我们假设 ROS 和 HIF-11 激活在 Cr(VI) 诱导的致癌作用中发挥重要作用。本研究将使用人支气管上皮BEAS-2B细胞和缺乏胸腺依赖性（T细胞）免疫功能的无胸腺雌性裸鼠（3-4周龄）。提出了三个具体目标。目标 1 将研究 Cr(VI) 诱导 ROS 生成的机制以及 ROS 在体外激活 HIF-11 和血管生成中的作用。 HIF-1 活性的调节可能发生在多个层面：转录、翻译和翻译后修饰。关于 Cr(VI) 在什么水平诱导 HIF-11 激活的问题仍然悬而未决。目标 2 将在细胞系统中回答这个问题。目标 3 将研究 ROS 和 HIF-1 信号在 Cr(VI) 诱导的体外细胞转化、体内肿瘤发生、肿瘤生长和转移中的作用。我们预计 Cr(VI) 通过 ROS 和 MAP 激酶 p38 激活 HIF-11 来诱导血管生成，促进 Cr(VI) 诱导的细胞转化、肿瘤发生、肿瘤生长和转移。。公共卫生相关性：六价铬 [Cr(VI)] 是一种已知的人类致癌物。 Cr(VI) 的致癌性已通过体外和体内研究得到充分证明。我们假设Cr(VI)诱导氧化应激并激活HIF-1血管生成信号通路，导致细胞转化、肿瘤发生、肿瘤生长和转移。该提案的目的是检验该假设。