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

Abstract

BACKGROUND:

Epidemiological observations have demonstrated that ambient fine particulate matter with dp < 2.5 μm (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.

• Authors: Ming-Yue Li, Li-Zhong Liu, Wende Li, Calvin S H Ng, Yi Liu, Angel W Y Kong, Zhili Zhao, Shanshan Wang, Haolong Qi, Hao Jia, Shucai Yang, Jing Du, Xiang Long, Rocky L K Ho, Ernest C W Chak, Innes Y P Wan, Tony S K Mok, Malcolm J Underwood, Nirmal Kumar Gali, Zhi Ning, George G Chen
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 38 Issue 1 Pg. 359 (Aug 16 2019) ISSN: 1756-9966 [Electronic] England
• PMID: 31420013 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• Lipoxygenase Inhibitors
• Nitrosamines
• Particulate Matter
• ALOX15B protein, human
• Arachidonate 15-Lipoxygenase

Topics

• Animals
• Apoptosis
• Arachidonate 15-Lipoxygenase (chemistry)
• Biomarkers, Tumor (metabolism)
• Carcinogenesis (chemically induced, metabolism, pathology)
• Case-Control Studies
• Cell Movement
• Cell Proliferation
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Lipoxygenase Inhibitors (adverse effects)
• Lung Neoplasms (enzymology, etiology, pathology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Nitrosamines (toxicity)
• Particulate Matter (adverse effects)
• Prognosis
• Smoking (adverse effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays