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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：
8240086
负责人：
Yong Lin
金额：
$ 42.71万
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/8240086
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 Co-Immunoprecipitations Coculture Techniques Conditioned Culture Media DNA Damage Development Dimethyl Sulfoxide Epidermal Growth Factor Receptor Epithelial Cells Epoxy Compounds 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 Process RNA Interference Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Signaling Research Risk Role Signal Transduction System TNF gene TNFRSF1A gene Testing Therapeutic Intervention Tobacco smoke Tobacco-Associated Carcinogen Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha United States Xenograft procedure air filter airway inflammation cancer cell cancer therapy carcinogenesis cell transformation cigarette smoke-induced cigarette smoking cytokine fetal bovine serum in vivo insight lung cancer prevention lung carcinogenesis lung development macrophage neutralizing antibody novel overexpression prevent public health relevance tumor

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。众所周知，香烟烟雾（CS）是肺癌的一个危险因素。炎症显然已成为导致肺癌和其他癌症发展的关键过程。然而，炎症调节影响癌症发展的基因靶点和途径尚未明确阐明。该应用建立在文献和我们小组的新兴研究的基础上，这些研究表明 MUC1 在炎症和癌变之间的重要作用。本申请的中心假设是，CS 引起的气道炎症会诱导 MUC1 表达，从而通过增强 EGFR 介导的 Akt 和细胞外信号调节激酶 (ERK) 途径触发肺癌的发展。这一假设将在三个具体目标中得到检验： 1. 确定促炎细胞因子 TNF？介导 CS 诱导的支气管上皮细胞中 MUC1 的表达，并且 MUC1 是否可以增强细胞转化； 2. 确定MUC1是否通过增强EGFR介导的Akt和ERK通路来促进CS诱导的支气管上皮细胞转化； 3. 探讨MUC1在CS诱导的肺癌、CS衍生致癌物苯并(a)芘(BaP)-和4-(甲基亚硝基氨基)-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中的作用。这项研究的成功完成将可能揭示涉及 Muc1 的 CS 诱导肺癌发生的新分子机制，并将为炎症如何影响细胞转化和肿瘤发展提供新的见解，并可能确定肺癌预防和干预治疗的新靶点。公共健康相关性：拟议的研究可能会揭示烟草烟雾诱发肺癌的新分子机制。这项研究的结果可能会带来肺癌预防和治疗的新策略。