Ambient fine particulate matter inhibits 15-lipoxygenases to promote lung carcinogenesis

BACKGROUND: Epidemiological observations have demonstrated that ambient fine particulate matter with d(p) < 2.5 μm (PM(2.5)) 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 PM(2.5) with lung carcinogenesis and to compare PM(2.5) with smoking carcinogens. METHODS: To study whether PM(2.5) 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 PM(2.5) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13046-019-1380-z) contains supplementary material, which is available to authorized users.