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Disruption of microRNA expression in human airway cells by diesel exhaust particles is linked to tumorigenesis-associated pathways.

Jardim MJ, Fry RC, Jaspers I, Dailey L, Diaz-Sanchez D - Environ. Health Perspect. (2009)

Bottom Line: Particulate matter (PM) is associated with adverse airway health effects; however, the underlying mechanism in disease initiation is still largely unknown.Specifically, 197 of 313 detectable miRNAs (62.9%) were either up-regulated or down-regulated by 1.5-fold.Alteration of miRNA expression profiles by environmental pollutants such as DEP can modify cellular processes by regulation of gene expression, which may lead to disease pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Human Studies Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Chapel Hill, North Carolina 27514, USA. jardim.melanie@epa.gov

ABSTRACT

Background: Particulate matter (PM) is associated with adverse airway health effects; however, the underlying mechanism in disease initiation is still largely unknown. Recently, microRNAs (miRNAs; small noncoding RNAs) have been suggested to be important in maintaining the lung in a disease-free state through regulation of gene expression. Although many studies have shown aberrant miRNA expression patterns in diseased versus healthy tissue, little is known regarding whether environmental agents can induce such changes.

Objectives: We used diesel exhaust particles (DEP), the largest source of emitted airborne PM, to investigate pollutant-induced changes in miRNA expression in airway epithelial cells. We hypothesized that DEP exposure can lead to disruption of normal miRNA expression patterns, representing a plausible novel mechanism through which DEP can mediate disease initiation.

Methods: Human bronchial epithelial cells were grown at air-liquid interface until they reached mucociliary differentiation. After treating the cells with 10 microg/cm(2) DEP for 24 hr, we analyzed total RNA for miRNA expression using microarray profile analysis and quantitative real-time polymerase chain reaction.

Results: DEP exposure changed the miRNA expression profile in human airway epithelial cells. Specifically, 197 of 313 detectable miRNAs (62.9%) were either up-regulated or down-regulated by 1.5-fold. Molecular network analysis of putative targets of the 12 most altered miRNAs indicated that DEP exposure is associated with inflammatory responses pathways and a strong tumorigenic disease signature.

Conclusions: Alteration of miRNA expression profiles by environmental pollutants such as DEP can modify cellular processes by regulation of gene expression, which may lead to disease pathogenesis.

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Related in: MedlinePlus

Identification of candidate molecular network for miRNAs most highly changed in response to DEP. We analyzed putative targets from miRNAs in Table 2 for significant pathway enrichment of molecular interactions and identified a significant interactome containing putative DEP-modulated gene products involved in tumorigenesis (highlighted in blue). Red represents putative DEP-induced transcripts, and green represents putative DEP-repressed transcripts; pathway enrichment is highlighted in blue; p < 10−47.
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f4-ehp-117-1745: Identification of candidate molecular network for miRNAs most highly changed in response to DEP. We analyzed putative targets from miRNAs in Table 2 for significant pathway enrichment of molecular interactions and identified a significant interactome containing putative DEP-modulated gene products involved in tumorigenesis (highlighted in blue). Red represents putative DEP-induced transcripts, and green represents putative DEP-repressed transcripts; pathway enrichment is highlighted in blue; p < 10−47.

Mentions: To further analyze the putative effects of differential miRNA expression profiles in DEP-exposed ALI cells, we again used TargetScan and miRDB to identify possible mRNA targets, with the same scoring criteria used above, for the remaining miRNAs listed in Table 2. These targets were then analyzed for enriched molecular networks. As such, we identified a total of 27 networks, the highest ranked of which was used for further examination (Figure 4). To better understand the potential health effects of the observed miRNA expression profile of DEP-exposed cells, we focused our analysis on putative disease signatures and functional relationships. Interestingly, the highest-ranked identified network was highly enriched for cancer, with an emphasis on tumorigenic processes.


Disruption of microRNA expression in human airway cells by diesel exhaust particles is linked to tumorigenesis-associated pathways.

Jardim MJ, Fry RC, Jaspers I, Dailey L, Diaz-Sanchez D - Environ. Health Perspect. (2009)

Identification of candidate molecular network for miRNAs most highly changed in response to DEP. We analyzed putative targets from miRNAs in Table 2 for significant pathway enrichment of molecular interactions and identified a significant interactome containing putative DEP-modulated gene products involved in tumorigenesis (highlighted in blue). Red represents putative DEP-induced transcripts, and green represents putative DEP-repressed transcripts; pathway enrichment is highlighted in blue; p < 10−47.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2801177&req=5

f4-ehp-117-1745: Identification of candidate molecular network for miRNAs most highly changed in response to DEP. We analyzed putative targets from miRNAs in Table 2 for significant pathway enrichment of molecular interactions and identified a significant interactome containing putative DEP-modulated gene products involved in tumorigenesis (highlighted in blue). Red represents putative DEP-induced transcripts, and green represents putative DEP-repressed transcripts; pathway enrichment is highlighted in blue; p < 10−47.
Mentions: To further analyze the putative effects of differential miRNA expression profiles in DEP-exposed ALI cells, we again used TargetScan and miRDB to identify possible mRNA targets, with the same scoring criteria used above, for the remaining miRNAs listed in Table 2. These targets were then analyzed for enriched molecular networks. As such, we identified a total of 27 networks, the highest ranked of which was used for further examination (Figure 4). To better understand the potential health effects of the observed miRNA expression profile of DEP-exposed cells, we focused our analysis on putative disease signatures and functional relationships. Interestingly, the highest-ranked identified network was highly enriched for cancer, with an emphasis on tumorigenic processes.

Bottom Line: Particulate matter (PM) is associated with adverse airway health effects; however, the underlying mechanism in disease initiation is still largely unknown.Specifically, 197 of 313 detectable miRNAs (62.9%) were either up-regulated or down-regulated by 1.5-fold.Alteration of miRNA expression profiles by environmental pollutants such as DEP can modify cellular processes by regulation of gene expression, which may lead to disease pathogenesis.

View Article: PubMed Central - PubMed

Affiliation: Human Studies Division, National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Chapel Hill, North Carolina 27514, USA. jardim.melanie@epa.gov

ABSTRACT

Background: Particulate matter (PM) is associated with adverse airway health effects; however, the underlying mechanism in disease initiation is still largely unknown. Recently, microRNAs (miRNAs; small noncoding RNAs) have been suggested to be important in maintaining the lung in a disease-free state through regulation of gene expression. Although many studies have shown aberrant miRNA expression patterns in diseased versus healthy tissue, little is known regarding whether environmental agents can induce such changes.

Objectives: We used diesel exhaust particles (DEP), the largest source of emitted airborne PM, to investigate pollutant-induced changes in miRNA expression in airway epithelial cells. We hypothesized that DEP exposure can lead to disruption of normal miRNA expression patterns, representing a plausible novel mechanism through which DEP can mediate disease initiation.

Methods: Human bronchial epithelial cells were grown at air-liquid interface until they reached mucociliary differentiation. After treating the cells with 10 microg/cm(2) DEP for 24 hr, we analyzed total RNA for miRNA expression using microarray profile analysis and quantitative real-time polymerase chain reaction.

Results: DEP exposure changed the miRNA expression profile in human airway epithelial cells. Specifically, 197 of 313 detectable miRNAs (62.9%) were either up-regulated or down-regulated by 1.5-fold. Molecular network analysis of putative targets of the 12 most altered miRNAs indicated that DEP exposure is associated with inflammatory responses pathways and a strong tumorigenic disease signature.

Conclusions: Alteration of miRNA expression profiles by environmental pollutants such as DEP can modify cellular processes by regulation of gene expression, which may lead to disease pathogenesis.

Show MeSH
Related in: MedlinePlus