Abstract
Long-term exposure to airborne PM2.5 is associated with increased lung cancer risk but the underlying mechanism remains unclear. We characterized global microRNA and mRNA expression in human bronchial epithelial cells exposed to PM2.5 organic extract and integrally analyzed microRNA-mRNA interactions. Foci formation and xenograft tumorigenesis in mice with NIH3T3 cells expressing genes targeted by microRNAs were performed to explore the oncogenic potential of these genes. We also detected plasma levels of candidate microRNAs in subjects exposed to different levels of air PM2.5 and examined the aberrant expression of genes targeted by these microRNAs in human lung cancer. Under our experimental conditions, treatment of cells with PM2.5 extract resulted in downregulation of 138 microRNAs and aberrant expression of 13 mRNAs (11 upregulation and 2 downregulation). In silico and biochemical analyses suggested SLC30A1, SERPINB2 and AKR1C1, among the upregulated genes, as target for miR-182 and miR-185, respectively. Ectopic expression of each of these genes significantly enhanced foci formation in NIH3T3 cells. Following subcutaneous injection of these cells into nude mice, fibrosarcoma were formed from SLC30A1- or SERPINB2-expressing cells. Reduced plasma levels of miR-182 were detected in subjects exposed to high level of PM2.5 than in those exposed to low level of PM2.5 (P = 0.043). Similar results were seen for miR-185 although the difference was not statistically significant (P = 0.328). Increased expressions of SLC30A1, SERPINB2 and AKR1C1 were detected in human lung cancer. These results suggest that modulation of miR-182 and miR-185 and their target genes may contribute to lung carcinogenesis attributable to PM2.5 exposure.
Highlights
Epidemiologic studies have associated increased lung cancer risk with long-term exposure to airborne particulate matters (PMs) including PM2.5 [1, 2], which contains mixture of crustal elements, metals, elemental carbon, inorganic ions, organic compounds, and biogenic species [2,3,4,5]
We examined the correlation between the expression of microRNAs and mRNAs to predict the potential targets of microRNAs and found 3 genes, SLC30A1, SERPINB2 and AKR1C1, whose expression was inversely correlated with miR-182 and miR-185 expression (Figure 1c)
We showed that downregulation of miR-182 and miR-185 in human bronchial epithelial (HBE) cells exposed to DMSO extracts of PM2.5 resulted in increased SLC30A1, SERPINB2 and AKR1C1 gene expression and ectopic expression of these genes can respectively lead to neoplastic transformation in NIH3T3 cells
Summary
Epidemiologic studies have associated increased lung cancer risk with long-term exposure to airborne particulate matters (PMs) including PM2.5 [1, 2], which contains mixture of crustal elements, metals, elemental carbon, inorganic ions (e.g., sulfate, nitrate, and ammonium), organic compounds (e.g., polycyclic aromatic hydrocarbons), and biogenic species [2,3,4,5]. Another study showed that single nucleotide polymorphisms in microRNA-processing genes modify the association between ambient pollutants including PM2.5 and soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 levels, which are associated with atherosclerosis and cardiovascular disease [16]. These findings imply that altered microRNA expression may play a role in PM2.5-induced diseases. Up to date, there is little experimental evidence showing the effects of exposure to airborne PM2.5 on microRNA expression in cells and its biological consequences
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