Ambient fine particulate matter inhibits 15-lipoxygenases to promote lung carcinogenesis
Ambient fine particulate matter inhibits 15-lipoxygenases to promote lung carcinogenesis
复制标题
环境细颗粒物抑制15-脂氧合酶促进肺癌发生
DOI：
10.1186/s13046-019-1380-z
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发表时间：
2019-08-16
影响因子：
11.3
通讯作者：
Chen, George G.
中科院分区：
文献类型：
--
作者：
Li, Ming-Yue;Liu, Li-Zhong;Chen, George G.
背景流行病学观察表明，d(p)<2.5μm的环境细颗粒物(PM2.5)是导致不吸烟者肺癌发病率增加的主要因素。然而，支持 PM2.5 与肺癌发生之间的关联以及将 PM2.5 与吸烟致癌物进行比较的实验数据非常有限。方法 为了研究 PM2.5 是否可以通过与吸烟致癌物质 4-甲基亚硝胺-1-3-吡啶基丁酮 (NNK) 类似的方式通过 15-脂氧合酶 (15-LOX) 还原来促进肺部肿瘤发生，用 NNK 或 PM2.5 处理正常肺上皮细胞和癌细胞，然后对细胞的细胞和分子谱进行表观遗传学和翻译后检查。这些数据在肺癌样本和小鼠肺癌模型中得到了验证。结果我们发现，与吸烟致癌物质NNK类似，PM2.5显着增强细胞增殖、迁移和侵袭，但降低15-脂氧合酶-1（15-LOX1）和15-脂氧合酶-2（15-LOX2）的水平，两者在肺癌组织中也明显降低。 15-LOX1/15-LOX2 过表达抑制 PM2.5/NNK 诱导的致癌细胞功能。植入 PM2.5 或 NNK 处理的 NCI-H23 细胞的小鼠中，肿瘤形成和生长明显更高/更快，并伴随着 15-LOX1/15-LOX2 的减少。此外，15-LOX1的表达在甲基化水平上受到PM2.5/NNK的表观遗传调节，而15-LOX1和15-LOX2都可以被一组PM2.5/NNK介导的microRNA显着抑制。结论 总体而言，PM2.5可作为吸烟致癌物NNK，通过抑制15-LOX1/15-LOX2诱导肺部肿瘤发生。
Background Epidemiological observations have demonstrated that ambient fine particulate matter with d(p) < 2.5 mu m (PM2.5) as the major factor responsible for the increasing incidence of lung cancer in never-smokers. However, there are very limited experimental data to support the association of PM2.5 with lung carcinogenesis and to compare PM2.5 with smoking carcinogens. Methods To study whether PM2.5 can contribute to lung tumorigenesis in a way similar to smoking carcinogen 4-methylnitrosamino-l-3-pyridyl-butanone (NNK) via 15-lipoxygenases (15-LOXs) reduction, normal lung epithelial cells and cancer cells were treated with NNK or PM2.5 and then epigenetically and post-translationally examined the cellular and molecular profiles of the cells. The data were verified in lung cancer samples and a mouse lung tumor model. Results We found that similar to smoking carcinogen NNK, PM2.5 significantly enhanced cell proliferation, migration and invasion, but reduced the levels of 15-lipoxygenases-1 (15-LOX1) and 15-lipoxygenases-2 (15-LOX2), both of which were also obviously decreased in lung cancer tissues. 15-LOX1/15-LOX2 overexpression inhibited the oncogenic cell functions induced by PM2.5/NNK. The tumor formation and growth were significantly higher/faster in mice implanted with PM2.5- or NNK-treated NCI-H23 cells, accompanied with a reduction of 15-LOX1/15-LOX2. Moreover, 15-LOX1 expression was epigenetically regulated at methylation level by PM2.5/NNK, while both 15-LOX1 and 15-LOX2 could be significantly inhibited by a set of PM2.5/NNK-mediated microRNAs. Conclusion Collectively, PM2.5 can function as the smoking carcinogen NNK to induce lung tumorigenesis by inhibiting 15-LOX1/15-LOX2.