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：
9016497
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 2018-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9016497
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 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 White Blood Cell Count procedure 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（由应用提供）：慢性肺部感染是肺癌的重要危险因素。累积数据表明，与没有肺部感染的吸烟者相比，患有慢性肺部感染的吸烟者患肺癌的风险更高。肺部感染与肺癌之间的分子联系是microRNA（miR）和促炎信号通路，例如AKT，NF-κB和STAT3。因此，化学预防剂靶向miR和促炎信号通路可以抑制肺部肿瘤的发生。该项目的主要目的是评估吲哚3-甲醇（I3C）和硅蛋白（SB）组合的有效性，两种广泛消耗的自然物质，以抑制慢性感染相关的肺癌并确定所涉及的机制。在初步研究中，我们开发了一种用于炎症驱动的肺癌的新型和便捷的小鼠模型，并显示了肺癌细胞系的体外研究表明，I3C加SB的增殖和凋亡效应与B平行B降低了促炎蛋白Akt，NF-κB和STAT3的促炎蛋白Akt和Mir-21和Mire-155，但per-155，但降低了促炎蛋白的激活。 miR-21和miR-155。因此，我们假设炎症驱动的肺部肿瘤起源可以被I3C和SB抑制，至少部分通过MIR-21和miR-155水平的调节与AKT，NF-KB和STAT3信号的抑制有关。该假设将通过以下三个目的来检验：特定目标1：评估I3C加SB对NNK加LPS诱导的小鼠肺腺癌，炎症环境和miR的效率。具体目标2：单独或组合抗MIR-21和抗MIR-155的效率，以抑制A/J小鼠中炎症驱动的肺肿瘤起源。特定目标3：阐明I3C加SB如何中断涉及AKT，NF-KB/STAT3和MIR-21/MIR155的炎症阳性反馈回路，从而抑制细胞的增殖和存活。影响/意义：这项研究的结果可以为肺癌化学预防的I3C加SB的未来临床试验建立基础，并更好地了解炎症驱动的肺肿瘤起源的分子事件。