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miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways
Lingyin Ge, … , Cory M. Hogaboam, Peter Chen
Lingyin Ge, … , Cory M. Hogaboam, Peter Chen
Published December 8, 2016
Citation Information: JCI Insight. 2016;1(20):e90301. https://doi.org/10.1172/jci.insight.90301.
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Research Article Pulmonology

miR-323a-3p regulates lung fibrosis by targeting multiple profibrotic pathways

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Abstract

Maladaptive epithelial repair from chronic injury is a common feature in fibrotic diseases, which in turn activates a pathogenic fibroblast response that produces excessive matrix deposition. Dysregulated microRNAs (miRs) can regulate expression of multiple genes and fundamentally alter cellular phenotypes during fibrosis. Although several miRs have been shown to be associated with lung fibrosis, the mechanisms by which miRs modulate epithelial behavior in lung fibrosis are lacking. Here, we identified miR-323a-3p to be downregulated in the epithelium of lungs with bronchiolitis obliterans syndrome (BOS) after lung transplantation, idiopathic pulmonary fibrosis (IPF), and murine bleomycin-induced fibrosis. Antagomirs for miR-323a-3p augment, and mimics suppress, murine lung fibrosis after bleomycin injury, indicating that this miR may govern profibrotic signals. We demonstrate that miR-323a-3p attenuates TGF-α and TGF-β signaling by directly targeting key adaptors in these important fibrogenic pathways. Moreover, miR-323a-3p lowers caspase-3 expression, thereby limiting programmed cell death from inducers of apoptosis and ER stress. Finally, we find that epithelial expression of miR-323a-3p modulates inhibitory crosstalk with fibroblasts. These studies demonstrate that miR-323a-3p has a central role in lung fibrosis that spans across murine and human disease, and downregulated expression by the lung epithelium releases inhibition of various profibrotic pathways to promote fibroproliferation.

Authors

Lingyin Ge, David M. Habiel, Phil M. Hansbro, Richard Y. Kim, Sina A. Gharib, Jeffery D. Edelman, Melanie Königshoff, Tanyalak Parimon, Rena Brauer, Ying Huang, Jenieke Allen, Dianhua Jiang, Adrianne A. Kurkciyan, Takako Mizuno, Barry R. Stripp, Paul W. Noble, Cory M. Hogaboam, Peter Chen

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Figure 6

miR-323a-3p attenuates apoptosis by suppressing CASP3 levels.

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miR-323a-3p attenuates apoptosis by suppressing CASP3 levels.
(A and B) ...
(A and B) 16HBE14o- cells transfected with miR-323a-3p mimic or control were stimulated with (A) staurosporine or (B) tunicamycin for 24 hours followed by measurement of caspase-3 activity. n = 3, *P < 0.05. (C) PCR and (D) Western blot for CASP3 in cells transfected with miR-323a-3p mimic or control. A representative blot is presented from 3 individual experiments. (E) Luciferase activity of HEK cells transfected with a reporter plasmid containing a chimeric firefly luciferase with the CASP3 3′ UTR. All data were normalized to Renilla luciferase activity. n = 3. Data are presented as box-and-whisker plots. The central horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate 1.5 times the interquartile range from the bottom and the top of the box. Statistical analysis in this figure was performed with the Student’s t test. RQ, relative quantification.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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