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

Abstract

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.

Progress on pivotal role and application of exosome in lung cancer carcinogenesis, diagnosis, therapy and prognosis

“…Significant associations are found with specific PM components such as PM 2.5 and lung cancer [ 21 ]. PM 2.5 concentration plays a dominant role in inducing lung cancer, which is consistent with the evidence that lung cancer incidence without tobacco smoking history is increasing in some large cities with air pollution problem [ 22 , 23 ]. The increased risk estimates of lung cancer are observed for each 10μg/m 3 increment in PM 2.5 concentration [ 24 ].…”

Exacerbation of Nanoparticle-Induced Acute Pulmonary Inflammation in a Mouse Model of Metabolic Syndrome

“…Ambient PM 2 . 5 exposure has been demonstrated in lung epithelial cells to inhibit ALOX-15, leading to enhances in markers of tumorigenesis though the mechanisms for this inhibition are unknown (66). Further, inhalation exposure of ozone also reduces ALOX-15 protein levels within the lung (61).…”

Regulation of ferroptosis by non‑coding RNAs in the development and treatment of cancer (Review)

“…LOX15-driven enzymatic generation of lipid peroxidation is a hallmark of ferroptotic signals ( 95 ). In the miR-17 family, miR-18a and miR-203 bind to four sites of the 3′-UTR in 15-LOX1, and miR-17, miR-20a, miR-20b, miR-106a, miR-106b, miR-93 and miR-590-3p bind to four sites of the 3′-UTR of 15-LOX2 ( 96 ). Oncogenic miR-219-2 ( 97 ) directly targets the 3′-UTR of 15-LOX, whereas miR-674-5p ( 98 ), miR-216a-3p ( 99 ) and miR-19a-3p/miR-125b-5p ( 100 ) regulate 5-LOX through directly targeting the 3′-UTR of 5-LOX.…”