Chemoprevention of inflammation-driven lung cancer

描述(申请人提供)：慢性肺部炎症是肺癌的重要危险因素。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。肺部炎症和肺癌之间的分子联系是microRNAs(MiRs)和促炎信号通路，如Akt、NF-κB和STAT3。因此，通过化学预防药物靶向miRs和促炎信号通路可以抑制肺癌的发生。该项目的主要目标是评估吲哚-3-甲醇(I3C)和水飞蓟宾(SB)这两种被广泛消费的天然植物化学物质联合抑制慢性炎症相关肺癌的效果，并确定相关机制。在初步研究中，我们建立了一种新的、简便的炎症驱动的小鼠肺癌模型，并在肺癌细胞系的体外研究中显示，I3C加Sb的抗增殖和凋亡作用与抑制促炎症蛋白Akt、NF-κB和STAT3的激活，下调miR-21和miR-155的表达，但上调分别针对miR-21和miR-155的PTEN和SHIP1的表达有关。因此，我们假设I3C加Sb至少部分可以通过调节miR-21和miR-155的水平以及抑制Akt、NF-kB和STAT3信号通路来抑制炎症驱动的肺肿瘤的发生。这一假说将通过以下三个目标进行验证：具体目标1：评价I3C+SB对NNK+LPS诱导的小鼠肺腺癌、炎症环境和miRs调节失调的疗效。特异性目的2：确定抗miR-21和抗miR-155单独或联合应用对A/J小鼠炎症诱导的肺癌发生的抑制作用。具体目标3：阐明I3C加SB如何阻断Akt、NF-kB/STAT3和miR-21/miR155等炎症正反馈回路，从而抑制细胞增殖和存活。影响/意义：这项研究的结果可能为I3C加SB用于肺癌化学预防的未来临床试验奠定基础，并为更好地理解炎症驱动的肺癌发生的分子事件提供更好的理解。

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.