Exposure to airborne PM2.5 suppresses microRNA expression and deregulates target oncogenes that cause neoplastic transformation in NIH3T3 cells

Oncotarget. 2015 Oct 6;6(30):29428-39. doi: 10.18632/oncotarget.5005.

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.

Keywords: PM2.5; bronchial epithelial cell; gene expression; microRNA expression; neoplastic transformation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 20-Hydroxysteroid Dehydrogenases / genetics
  • 20-Hydroxysteroid Dehydrogenases / metabolism
  • Air Pollutants / toxicity*
  • Animals
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Bronchi / drug effects*
  • Bronchi / metabolism
  • Bronchi / pathology
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / chemically induced*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Computer Simulation
  • Down-Regulation
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Fibroblasts / drug effects*
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibroblasts / transplantation
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / blood
  • Lung Neoplasms / chemically induced*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / blood
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • NIH 3T3 Cells
  • Oncogenes*
  • Particulate Matter / toxicity*
  • Pilot Projects
  • Plasminogen Activator Inhibitor 2 / genetics
  • Plasminogen Activator Inhibitor 2 / metabolism
  • Time Factors
  • Transfection

Substances

  • Air Pollutants
  • Biomarkers, Tumor
  • Cation Transport Proteins
  • MicroRNAs
  • Mirn182 microRNA, human
  • Particulate Matter
  • Plasminogen Activator Inhibitor 2
  • SLC30A1 protein, human
  • 20-Hydroxysteroid Dehydrogenases
  • 3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase