Mechanistic Studies on Lung Cancer Prevention by Tea Polyphenols

茶多酚预防肺癌的机理研究

• 批准号: 7845211
• 负责人: CHUNG S. YANG
• 金额: $ 1.92万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845211
• 关键词: A/J Mouse; Address; Adenocarcinoma; Affinity; Affinity Chromatography; Allografting; Animal Model; Animal Welfare; Apoptosis; Apoptotic; Attention; Bibliography; Binding; Biological; Budgets; Butanones; Cancer Prevention Trial; Cancer cell line; Cell Line; Chemoprevention; Chemopreventive Agent; Chin; Collaborations; Country; Critiques; DNA Microarray Chip; Dose; Engineering; Environment; Environmental Impact; Epigallocatechin Gallate; Equipment; Event; Future; Gene Targeting; Genes; Genomics; Goals; Growth; H1299; Human; IACUC; Immunohistochemistry; In Vitro; Inhibition of Apoptosis; International; Lead; Learning; Lesion; Lung; MAPK8 gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Mediating; Minnesota; Modeling; Molecular; Molecular Target; Mus; Nature; Oxidative Stress; Pathology; Pathway interactions; Pharmacodynamics; Play; Premalignant; Preventive; Principal Investigator; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Relative (related person); Research; Research Ethics Committees; Resistance; Resources; Role; Sampling; Signal Transduction; Signal Transduction Pathway; Smoker; Staging; System; Tea; Testing; Time; Tissues; Universities; Vascular Endothelial Growth Factors; Vertebrates; Western Blotting; Work; Xenograft Model; Xenograft procedure; Yang; abstracting; adenoma; angiogenesis; base; cancer cell; cancer chemoprevention; cancer prevention; carcinogenesis; cellular engineering; design; dietary constituent; expiration; gain of function; gallocatechol; human subject; in vivo; indexing; knock-down; loss of function; lung cancer prevention; lung carcinogenesis; lung tumorigenesis; overexpression; polyphenol; programs; research study; response; treatment effect; tumor; tumor growth; tumor progression

Our long-term goal is to understand the cancer preventive activities of tea constituents and their applications to human cancer prevention. The cancer preventive activity of tea polyphenols has been demonstrated in animal models, but the mechanisms of action are not clearly understood. This project aims to elucidate the mechanisms of lung cancer prevention by (-)-epigallocatechin-3-gallate (EGCG), the major green tea polyphenol. Our goal is to establish an integrated in vitro and in vivo experimental system to test our central hypothesis that EGCG inhibits lung carcinogenesis by binding to specific target molecules which are vital to carcinogenesis and this binding triggers alterations in signal transduction pathways that lead to growth inhibition and apoptosis of premalignant and malignant cells. In order to effectively test our hypothesis, we plan to use both in vitro and in vivo experimental systems. The specific aims are as follows: 1. Establish and compare in vivo (xenograft & allograft) and in vitro experimental systems with lung cancer cell lines and study the mechanisms of action of EGCG. Lung cancer cell lines H1299 (human) and CL13 and CL30 (mouse) will be studied in culture and in xenografts/allografts. The effects of EGCG treatment on tumor growth, apoptosis, angiogenesis, and related molecular changes (e.g., ERK1/2, AKT, ASK1, JNK, VEGF, and oxidative stress parameters) will be compared in vivo vs. in vitro. 2. Identify direct molecular targets of EGCG by affinity-proteomics and functional studies. To identify direct molecular targets for EGCG, we will use affinity chromatography and mass spectrometry in collaboration with Dr. Zigang Dong at the University of Minnesota. The functional roles of the putative EGCG target proteins in mediating the action of EGCG will be studied with loss or gain of function experiments in engineered cells and in a xenograft/allograft model established in Aim 1. 3. Elucidate the mechanisms of cancer prevention by EGCG in a 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK)-induced lung carcinogenesis model in A/J mice. Adenoma-bearing mice will receive long- or short-term treatment with EGCG. The cellular and molecular changes related to the inhibition of tumor progression will be investigated using immunohistochemistry, Western blots, and other approaches. We will test specific hypotheses developed based on results from Aims 1 and 2 concerning putative EGCG molecular targets and related molecular events. A better understanding of the mechanisms of the cancer preventive action of EGCG and the dose- response relationship will help us to design future lung cancer prevention trials in humans, for example, in ex-smokers.

我们的长期目标是了解茶成分的癌症预防活动及其对预防人类癌症的应用。在动物模型中已经证明了茶多酚的癌症预防活性，但作用机理尚未清楚地理解。该项目旨在通过（ - ） - 绿茶多酚（EGCG）（EGCG）阐明肺癌预防的机制。我们的目标是建立一个整合体外和体内实验系统，以测试我们的中心假设，即EGCG通过与特定的靶标分子结合来抑制肺癌发生，这对癌变至关重要，这对于癌变至关重要，而这种结合触发了信号转导途径的改变，从而导致生长抑制和非洲细胞的细胞。为了有效地检验我们的假设，我们计划同时使用体内和体内实验系统。具体目的如下： 1。建立和比较体内（异种移植物和同种异体移植）和肺癌细胞系的体外实验系统，并研究EGCG的作用机理。肺癌细胞系H1299（人）和CL13和CL30（小鼠）将在培养和异种移植物/同种异体移植中进行研究。 EGCG治疗对肿瘤生长，凋亡，血管生成和相关分子变化的影响（例如ERK1/2，AKT，ASK1，JNK，VEGF和氧化应激参数）将在体内与体内进行比较。 2。通过亲和力蛋白质组学和功能研究确定EGCG的直接分子靶标。为了确定EGCG的直接分子靶标，我们将与明尼苏达大学的Zigang Dong博士合作使用亲和力色谱和质谱。假定的EGCG靶蛋白在介导EGCG作用中的功能作用将在工程细胞中的功能实验以及AIM 1中建立的异种移植/同种异体移植模型中进行研究。 3。阐明了EGCG在4-（甲基硝基氨基氨基）-1-（3-吡啶基）-1-丁酮（NNK）诱导的肺癌发生模型中预防癌症的机制。含有腺瘤的小鼠将接受EGCG的长期或短期治疗。与抑制肿瘤进展有关的细胞和分子变化将使用免疫组织化学，蛋白质印迹和其他方法研究。 我们将根据目标1和2的结果来检验特定的假设，这些假设与推定的EGCG分子靶标和相关的分子事件有关。 更好地了解EGCG癌症预防作用的机制和剂量反应关系将有助于我们在人类中设计未来的预防肺癌预防试验，例如在前吸烟者中。