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，化疗预防药物靶向miRs和促炎信号通路可以抑制肺肿瘤的发生。本项目的主要目的是评估吲哚- 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联合使用对慢性炎症相关肺癌的抑制作用，并确定其机制。在初步研究中，我们开发了一种新的、简便的炎症驱动肺癌小鼠模型，并在肺癌细胞系的体外研究中显示，I3C + SB的细胞增殖和凋亡作用是平行的，因为它降低了促炎蛋白Akt、NF-κB和STAT3的激活，下调了miR-21和miR-155，上调了miR-21和miR-155的靶点PTEN和SHIP1。因此，我们假设I3C + SB可以通过调节miR-21和miR-155水平，抑制Akt、NF-kB和STAT3信号通路，至少在一定程度上抑制炎症驱动的肺肿瘤发生。具体目的1：评估I3C + SB对NNK + lps诱导的小鼠肺腺癌、炎症环境和miRs失调的疗效。特异性目的2：确定anti-miR-21和anti-miR-155单独或联合抑制A/J小鼠炎症驱动的肺肿瘤发生的功效。特异性目的3：阐明I3C + SB如何阻断涉及Akt、NF-kB/STAT3和miR-21/miR155的炎症正反馈回路，从而抑制细胞增殖和存活。影响/意义：本研究结果可为未来I3C联合SB用于肺癌化学预防的临床试验奠定基础，并为更好地了解炎症驱动肺肿瘤发生的分子事件提供依据。

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.