Chemoprevention of inflammation-driven lung cancer

炎症驱动的肺癌的化学预防

基本信息

批准号：
8815111
负责人：
Fekadu Kassie
金额：
$ 31.54万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8815111
关键词：
A/J Mouse Alveolar Macrophages Animal Model Animals Ants Apoptosis Apoptotic Blood Butanones Cancer Etiology Cancer cell line Carcinogens Cell Line Cell Proliferation Cell Survival Cells Chemoprevention Chemopreventive Agent Chronic Clinical Trials Complex Data Development Diet Differential white blood cell count procedure Disease Down-Regulation Dust Event Feedback Future Gene Targeting Goals Growth Health Histologic Human In Vitro Indole-3-Carbinol Inflammation Inflammatory Irrigation Link Lipopolysaccharides Liquid substance Lung Lung Adenocarcinoma Lung Neoplasms Macrophage Activation Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung MicroRNAs Modeling Molecular Molecular Genetics Mus NF-kappa B Oligonucleotides Oncogenic PTEN gene Phytochemical Plants Premalignant Preventive Property Proto-Oncogene Proteins c-akt Pulmonary Inflammation Risk Risk Factors Role STAT3 gene Signal Pathway Signal Transduction Smoker Testing Therapeutic Agents Tobacco smoke Tumor Suppressor Proteins Tumor Tissue Up-Regulation base cancer cell cancer chemoprevention chemokine cytokine density genetic approach high risk in vitro Model inhibitor/antagonist lung tumorigenesis macrophage mortality mouse model neoplastic cell novel silibinin

项目摘要

DESCRIPTION (provided by applicant): Chronic pulmonary inflammation is an important risk factor for lung cancer. Accumulating data have shown that smokers with chronic pulmonary inflammation have a higher risk of developing lung cancer as compared to smokers without pulmonary inflammation. Molecular links between pulmonary inflammation and lung cancer are microRNAs (miRs) and pro-inflammatory signaling pathways such as Akt, NF-κB and STAT3. Therefore, targeting of miRs and pro-inflammatory signaling pathways by chemo preventive agents could suppress lung tumor genesis. The main goal of this project is to assess the efficacy of combinations of indole- 3-carbinol (I3C) and silibinin (SB), two widely consumed naturally occurring phytochemicals, to inhibit chronic inflammation-related lung cancer and determine the mechanisms involved. In preliminary studies, we developed a novel and facile mouse model for inflammation-driven lung cancer and showed in in vitro studies with lung cancer cell lines that the ant proliferative and apoptotic effects of I3C plus SB were paralleled b decreased activation of the pro-inflammatory proteins Akt, NF-κB and STAT3, down-regulation of miR-21 and miR-155, but up-regulation of PTEN and SHIP1, targets for miR-21 and miR-155, respectively. Therefore, we hypothesized that inflammation-driven lung tumor genesis could be inhibited by I3C plus SB, at least in part, via modulation of miR-21 and miR-155 levels in association with inhibition of Akt, NF-kB and STAT3 signaling. This hypothesis will be tested by the following three Aims: Specific Aim 1: Evaluate the efficacy of I3C plus SB against NNK plus LPS-induced mouse lung adenocarcinoma, inflammatory milieu and dysregulation of miRs. Specific Aim 2: Determine the efficacy of anti-miR-21 and anti-miR-155, alone or in combination, to inhibit inflammation-driven lung tumor genesis in A/J mice. Specific Aim 3: Elucidate how I3C plus SB interrupts the inflammatory positive feedback loop involving Akt, NF-kB/STAT3, and miR-21/miR155 and thus inhibits cell proliferation and survival. Impact/Significance: The results of this study could establish the basis for future clinical trials of I3C plus SB for lung cancer chemoprevention and provide a better understanding of the molecular events underlying inflammation-driven lung tumor genesis.

描述（申请人提供）：慢性肺部炎症是肺癌的一个重要危险因素，越来越多的数据表明，与没有肺部炎症的吸烟者相比，患有慢性肺部炎症的吸烟者患肺癌的风险更高。肺癌和微小 RNA (miR) 以及 Akt、NF-κB 和 STAT3 等促炎症信号通路有关，因此，化疗预防药物靶向 miR 和促炎症信号通路可以抑制肺癌。该项目的主要目标是评估吲哚-3-甲醇（I3C）和水飞蓟宾（SB）这两种广泛消耗的天然植物化学物质的组合抑制慢性炎症相关肺癌的功效并确定其机制。在初步研究中，我们针对炎症驱动的肺癌开发了一种新颖且简便的小鼠模型，并在肺癌细胞系的体外研究中表明，I3C plus 具有增殖和凋亡作用。 SB 与促炎蛋白 Akt、NF-κB 和 STAT3 的激活减少，miR-21 和 miR-155 下调，但 miR-21 和 miR-155 靶标 PTEN 和 SHIP1 上调因此，我们发现 I3C 加 SB 可以至少部分地通过调节 miR-21 和 miR-21 来抑制炎症驱动的肺肿瘤发生。 miR-155 水平与 Akt、NF-kB 和 STAT3 信号传导抑制相关该假设将通过以下三个目标进行检验：具体目标 1：评估 I3C 加 SB 对 NNK 加 LPS 诱导的小鼠肺腺癌的功效。具体目标 2：确定抗 miR-21 和抗 miR-155 单独或联合使用的功效。组合，抑制 A/J 小鼠中炎症驱动的肺部肿瘤发生。具体目标 3：阐明 I3C 加 SB 如何中断涉及 Akt、NF-kB/STAT3 和 miR-21/miR155 的炎症正反馈环，从而抑制细胞。影响/意义：本研究的结果可以为未来 I3C 加 SB 用于肺癌化学预防的临床试验奠定基础，并提供对分子事件的更好理解。潜在的炎症驱动的肺部肿瘤发生。