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Bridging Inflammation and Cigarette Smoke-associated Lung Carcinogenesis by MUC1

MUC1 桥接炎症和香烟烟雾相关的肺癌发生

基本信息

批准号：
7986321
负责人：
Yong Lin
金额：
$ 45.61万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
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/7986321
关键词：
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide Analysis of Variance Apoptosis Benzo(a)pyrene Bronchoalveolar Lavage Fluid Butanones Cancer Etiology Cancer Model Cancer cell line Carcinogens Cell Survival Cells Cessation of life Chemosensitization Chronic Cigarette Co-Immunoprecipitations Coculture Techniques Conditioned Culture Media DNA Damage Development Dimethyl Sulfoxide Epidermal Growth Factor Receptor Epithelial Cells Epoxy Compounds Extracellular Signal Regulated Kinases Figs - dietary Gene Targeting Genetic Glycols Human In Vitro Inflammation Inflammatory Knockout Mice Lead Lesion Link Literature Lung Lung Inflammation Lung Neoplasms MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Glycoproteins Methylnitrosourea Mitogen-Activated Protein Kinases Modeling Molecular Molecular Target Mucin-1 Staining Method Mus Non-Small-Cell Lung Carcinoma Nude Mice Organ Outcome Study Particulate Particulate Matter Pathogenesis Pathway interactions Prevention therapy Preventive Intervention Process RNA Interference Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Research Risk Role Signal Transduction Smoke System TNF gene TNFRSF1A gene Testing Therapeutic Intervention Tobacco Tobacco-Associated Carcinogen Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha United States Xenograft procedure air filter airway inflammation cancer cell carcinogenesis cell transformation cigarette smoke-induced cigarette smoking cigarette smoking cytokine fetal bovine serum human TNFRSF1A protein in vivo insight lung cancer prevention lung carcinogenesis lung development macrophage neutralizing antibody novel overexpression prevent public health relevance tumor tumor necrosis factor alpha receptor

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer-related death in the United States. Cigarette smoke (CS) is a well- known risk for lung cancer. Inflammation has clearly emerged as a key process contributing to the development of lung and other cancers. However, the gene targets and pathways modulated by inflammation that impact cancer development have not been clearly elucidated. This application builds on emerging studies from the literature and by our group that implicate an important role for MUC1 in linking inflammation and carcinogenesis. The central hypothesis of this application is that airway inflammation resulting from CS induces MUC1 expression, which triggers lung cancer development through potentiation of the EGFR- mediated Akt and extracellular signal-regulated kinases (ERK) pathways. This hypothesis will be tested in the three Specific Aims: 1. To determine if the pro-inflammatory cytokine TNF? mediates CS-induced MUC1 expression in bronchial epithelial cells and if MUC1 potentiates cell transformation; 2. To determine if MUC1 facilitates CS-induced bronchial epithelial cell transformation through potentiation of the EGFR-mediated Akt and ERK pathways; 3. To investigate the role of MUC1 in CS-induced lung carcinogenesis with CS-derived carcinogen benzo(a)pyrene (BaP)- and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced A/J lung cancer models and in a xenografted human lung tumor model in nude mice. Successful completion of this study will likely reveal a new molecular mechanism of CS-induced lung carcinogenesis that involves Muc1 and will provide new insights into how inflammation influences cell transformation and tumor development and could identify novel targets for prevention and intervention therapy for lung cancer. PUBLIC HEALTH RELEVANCE: The proposed research will likely unravel a new molecular mechanism of tobacco smoke-induced lung carcinogenesis. The outcome from this study may lead to new strategies for lung cancer prevention and therapy.

描述（由申请人提供）：肺癌是美国癌症相关死亡的主要原因。吸烟是众所周知的肺癌危险因素.炎症显然已成为促成肺癌和其他癌症发展的关键过程。然而，影响癌症发展的炎症调节的基因靶点和途径尚未明确阐明。这项应用建立在文献和我们小组的新研究基础上，这些研究暗示MUC 1在连接炎症和癌变中起着重要作用。本申请的中心假设是由CS引起的气道炎症诱导MUC 1表达，其通过EGFR介导的Akt和细胞外信号调节激酶（ERK）途径的增强而触发肺癌发展。这一假设将在以下三个具体目标中得到检验：1.为了确定是否促炎细胞因子TNF？介导CS诱导的MUC 1在支气管上皮细胞中的表达，并且如果MUC 1增强细胞转化; 2.确定MUC 1是否通过增强EGFR介导的Akt和ERK途径促进CS诱导的支气管上皮细胞转化; 3.研究MUC 1在CS诱导的肺癌发生中的作用，采用CS衍生致癌物苯并（a）芘（BaP）和4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）诱导的A/J肺癌模型和裸鼠异种移植人肺肿瘤模型。这项研究的成功完成可能会揭示CS诱导的肺癌发生的新分子机制，涉及Muc 1，并将为炎症如何影响细胞转化和肿瘤发展提供新的见解，并可能为肺癌的预防和干预治疗确定新的靶点。公共卫生相关性：拟议中的研究可能会揭示烟草烟雾诱导肺癌发生的新分子机制。这项研究的结果可能会导致肺癌预防和治疗的新策略。