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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

Subnetworks of select putative DEP-regulated gene transcripts show an enrichment of inflammatory response. Gene networks displaying putative interactions using potential gene targets of (A) miR-513a-5p (p < 10−27), (B) miR-494 (p < 10−49), and (C) miR-96 (p < 10−49). Solid-colored shapes indicate molecules identified as putative targets for each respective miRNA. Green indicates putative transcripts that are repressed, and red indicates putative gene targets that may be up-regulated; pathway enrichment is highlighted in blue.
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f3-ehp-117-1745: Subnetworks of select putative DEP-regulated gene transcripts show an enrichment of inflammatory response. Gene networks displaying putative interactions using potential gene targets of (A) miR-513a-5p (p < 10−27), (B) miR-494 (p < 10−49), and (C) miR-96 (p < 10−49). Solid-colored shapes indicate molecules identified as putative targets for each respective miRNA. Green indicates putative transcripts that are repressed, and red indicates putative gene targets that may be up-regulated; pathway enrichment is highlighted in blue.

Mentions: To determine the biological relevance of the identified miRNAs, networks were mapped for each of the putative input miRNA targets for three significantly altered miRNAs (Figure 3). We assessed the potential biological functions of select miRNAs by identifying putative miRNA targets using TargetScan and miRDB for miR-513a-5p, miR-494, miR-96, and miR-923. Targets were chosen based on a reported context score of ≥ 80 (miRDB) or a score of ≤ −0.5 (TargetScan); neither program generated target mRNAs that fit our criteria for miR-923, so it was excluded from any further analysis. Identified molecular networks were highly enriched for inflammatory responses that correlated well with canonical signaling pathways, such as interleukin (IL)-8, nuclear factor kappa B (NF-κB), and chemokine (C-X-C motif) receptor 4, where these targets could be acting.


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)

Subnetworks of select putative DEP-regulated gene transcripts show an enrichment of inflammatory response. Gene networks displaying putative interactions using potential gene targets of (A) miR-513a-5p (p < 10−27), (B) miR-494 (p < 10−49), and (C) miR-96 (p < 10−49). Solid-colored shapes indicate molecules identified as putative targets for each respective miRNA. Green indicates putative transcripts that are repressed, and red indicates putative gene targets that may be up-regulated; pathway enrichment is highlighted in blue.
© Copyright Policy - public-domain
Related In: Results  -  Collection

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

f3-ehp-117-1745: Subnetworks of select putative DEP-regulated gene transcripts show an enrichment of inflammatory response. Gene networks displaying putative interactions using potential gene targets of (A) miR-513a-5p (p < 10−27), (B) miR-494 (p < 10−49), and (C) miR-96 (p < 10−49). Solid-colored shapes indicate molecules identified as putative targets for each respective miRNA. Green indicates putative transcripts that are repressed, and red indicates putative gene targets that may be up-regulated; pathway enrichment is highlighted in blue.
Mentions: To determine the biological relevance of the identified miRNAs, networks were mapped for each of the putative input miRNA targets for three significantly altered miRNAs (Figure 3). We assessed the potential biological functions of select miRNAs by identifying putative miRNA targets using TargetScan and miRDB for miR-513a-5p, miR-494, miR-96, and miR-923. Targets were chosen based on a reported context score of ≥ 80 (miRDB) or a score of ≤ −0.5 (TargetScan); neither program generated target mRNAs that fit our criteria for miR-923, so it was excluded from any further analysis. Identified molecular networks were highly enriched for inflammatory responses that correlated well with canonical signaling pathways, such as interleukin (IL)-8, nuclear factor kappa B (NF-κB), and chemokine (C-X-C motif) receptor 4, where these targets could be acting.

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