Lung cancer is the leading cause of cancer related deaths worldwide. The present study investigated the effects of naproxen (NSAID) on lung adenocarcinoma in spontaneous lung cancer mouse model. Six-week-old transgenic Kras^G12V mice (n = 20; male + female) were fed modified AIN-76A diets containing naproxen (0/400 ppm) for 30 wk and euthanized at 36 wk of age. Lungs were evaluated for tumor incidence, multiplicity, and histopathological stage (adenoma and adenocarcinoma). Lung tumors were noticeable as early as 12 wk of age exclusively in the Kras^G12V mice. By 36 wk age, 100% of Kras^G12V mice on control diet developed lung tumors, mostly adenocarcinomas. Kras^G12V mice fed control diet developed 19.8 ± 0.96 (Mean ± SEM) lung tumors (2.5 ± 0.3 adenoma, 17.3 ± 0.7 adenocarcinoma). Administration of naproxen (400 ppm) inhibited lung tumor multiplicity by ∼52% (9.4 ± 0.85; P < 0001) and adenocarcinoma by ∼64% (6.1 ± 0.6; P < 0001), compared with control-diet-fed mice. However, no significant difference was observed in the number of adenomas in either diet, suggesting that naproxen was more effective in inhibiting tumor progression to adenocarcinoma. Biomarker analysis showed significantly reduced inflammation (COX-2, IL-10), reduced tumor cell proliferation (PCNA, cyclin D1), and increased apoptosis (p21, caspase-3) in the lung tumors exposed to naproxen. Decreased serum levels of PGE₂ and CXCR4 were observed in naproxen diet fed Kras^G12V mice. Gene expression analysis of tumors revealed a significant increase in cytokine modulated genes (H2-Aa, H2-Ab1, Clu), which known to further modulate the cytokine signaling pathways. Overall, the results suggest a chemopreventive role of naproxen in inhibiting spontaneous lung adenocarcinoma formation in Kras^G12V mice.

肺癌是全球癌症相关死亡的主要原因。本研究调查了萘普生 (NSAID) 对自发性肺癌小鼠模型中肺腺癌的影响。六周大的转基因 Kras ^G12V小鼠（n  = 20；雄性 + 雌性）喂食含有萘普生（0/400 ppm）的改良 AIN-76A 饮食 30 周，并在 36 周龄时实施安乐死。评估肺的肿瘤发生率、多样性和组织病理学分期（腺瘤和腺癌）。肺肿瘤早在 12 周龄时就在 Kras ^G12V小鼠中显着。到 36 周龄时，100%^接受对照饮食的 Kras ^G12V小鼠出现肺部肿瘤，主要是腺癌。克拉斯^G12V喂食对照饮食的小鼠发生了 19.8 ± 0.96（平均值 ± SEM）肺肿瘤（2.5 ± 0.3 腺瘤，17.3 ± 0.7 腺癌）。与对照饮食喂养的小鼠相比，萘普生 (400 ppm) 的给药抑制了约 52% (9.4 ± 0.85; P < 0001) 的肺肿瘤多样性和约64% (6.1 ± 0.6; P < 0001) 的腺癌。然而，两种饮食中的腺瘤数量均未观察到显着差异，表明萘普生在抑制肿瘤进展为腺癌方面更有效。生物标志物分析显示，暴露于萘普生的肺肿瘤中炎症显着减少（COX-2、IL-10）、肿瘤细胞增殖减少（PCNA、细胞周期蛋白 D1）和细胞凋亡增加（p21、caspase-3）。降低血清 PGE ₂水平在用萘普生饮食喂养的 Kras ^G12V小鼠中观察到 CXCR4 和 CXCR4 。肿瘤的基因表达分析显示细胞因子调节基因（H2-Aa、H2-Ab1、Clu）显着增加，这些基因已知可进一步调节细胞因子信号通路。总体而言，结果表明萘普生在抑制 Kras ^G12V小鼠中自发性肺腺癌形成方面具有化学预防作用。