Chemoprevention of inflammation-driven lung cancer

描述（由申请人提供）：慢性肺部炎症是肺癌的重要风险因素。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microRNA（miR）和促炎信号通路如Akt、NF-κB和STAT 3。因此，通过化学预防剂靶向miR和促炎信号传导通路可以抑制肺肿瘤发生。该项目的主要目标是评估吲哚-3-甲醇（I3 C）和水飞蓟宾（SB）（两种广泛使用的天然植物化学物质）组合抑制慢性炎症相关肺癌的疗效，并确定相关机制。在初步研究中，我们开发了一种新的和简单的炎症驱动的肺癌小鼠模型，并在肺癌细胞系的体外研究中显示，I3 C加SB的抗增殖和凋亡作用是显著的，降低了促炎蛋白Akt、NF-κB和STAT 3的活化，下调了miR-21和miR-155，但上调了PTEN和SHIP 1，分别针对miR-21和miR-155。因此，我们假设炎症驱动的肺肿瘤发生可以被I3 C加SB抑制，至少部分是通过调节miR-21和miR-155水平以及抑制Akt、NF-kB和STAT 3信号传导来抑制的。具体目标1：评价I3 C加SB对NNK加LPS诱导的小鼠肺腺癌、炎性环境和miR失调的疗效。具体目标二：确定抗miR-21和抗miR-155单独或组合抑制A/J小鼠中炎症驱动的肺肿瘤发生的功效。具体目标3：阐明I3 C加SB如何中断涉及Akt、NF-kB/STAT 3和miR-21/miR 155的炎症正反馈回路，从而抑制细胞增殖和存活。影响/意义：本研究的结果可以为I3 C加SB用于肺癌化学预防的未来临床试验奠定基础，并提供对炎症驱动的肺肿瘤发生的分子事件的更好理解。

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.