Profibrotic Role of miR-154 in Pulmonary Fibrosis

Milošević, Jadranka; Pandit, Kusum; Magister, Marcus J.; Rabinovich, Einat I.; Ellwanger, Daniel C.; Yu, Guoying; Vuga, Louis J.; Weksler, Benny; Benos, Panayiotis V.; Gibson, Kevin F.; McMillan, Michael; Kahn, Michaël; Kaminski, Naftali

doi:10.1165/rcmb.2011-0377oc

Cited by 159 publications

(175 citation statements)

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“…Several of the miRNAs predicted as regulating developmental genes are also DE in IPF, often in the opposite direction. These results add to a growing body of literature that suggests that miRNAs involved in development may play an opposite role in diseases (33,38). mirDREM, available from the supporting website (www.sb.cs.…”

Section: Discussionmentioning

confidence: 53%

Reconstructing dynamic microRNA-regulated interaction networks

Schulz

Pandit

Cardenas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The regulation of gene expression in cells, including by microRNAs (miRNAs), is a dynamic process. Current methods for identifying miRNA targets by combining sequence and miRNA and mRNA expression data do not adequately use the temporal information and thus miss important miRNAs and their targets. We developed the MIRna Dynamic Regulatory Events Miner (mirDREM), a probabilistic modeling method that uses input-output hidden Markov models to reconstruct dynamic regulatory networks that explain how temporal gene expression is jointly regulated by miRNAs and transcription factors. We measured miRNA and mRNA expression for postnatal lung development in mice and used mirDREM to study the regulation of this process. The reconstructed dynamic network correctly identified known miRNAs and transcription factors. The method has also provided predictions about additional miRNAs regulating this process and the specific developmental phases they regulate, several of which were experimentally validated. Our analysis uncovered links between miRNAs involved in lung development and differentially expressed miRNAs in idiopathic pulmonary fibrosis patients, some of which we have experimentally validated using proliferation assays. These results indicate that some disease progression pathways in idiopathic pulmonary fibrosis may represent partial reversal of lung differentiation.systems biology | network modeling

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Section: Discussionmentioning

confidence: 53%

Reconstructing dynamic microRNA-regulated interaction networks

Schulz

Pandit

Cardenas

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Although we demonstrated the functional role of miR-326 using in vitro model of EMT, contradictory reports on EMT in IPF (30) indicate that these results may not be directly extrapolated to pulmonary fibrosis. However, many recent reports suggest the importance of miRNAs in pulmonary fibrosis (31)(32)(33), indicating the potential therapeutic importance of miRNAs in IPF. Because TGF-b1-induced fibrosis is important in many diseases, it is likely that our findings may have future clinical applications.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-326 Regulates Profibrotic Functions of Transforming Growth Factor-β in Pulmonary Fibrosis

Das

Kumar

Negi

et al. 2014

Am J Respir Cell Mol Biol

148

122

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Idiopathic pulmonary fibrosis (IPF) is a fatal disorder resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor (TGF)-b has a wellestablished role in lung fibrosis, clinical experience with neutralizing antibodies to TGF-b has been disappointing, and strategies to directly suppress TGF-b1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-b1 regulation and to validate the role of miR-326 in pulmonary fibrosis.We show that hsa-miR-326 regulates TGF-b1 expression and that hsa-miR-326 levels are inversely correlated to TGF-b1 protein levels in multiple human cell lines. The increase in TGF-b1 expression during the progression of bleomycin-induced lung fibrosis in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-b1 expression and attenuate the fibrotic response. Moreover, human IPF lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-b signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-b1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis.

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“…In this study, we investigated the effect of XAV939 on bleomycin-induced lung fibrosis and tried to reveal detailed pathogenic mechanisms. XAV939 has also been previously used to block the canonical Wnt pathway induced by miRNA 154, which participates in lung fibrosis and seems to upregulate the canonical Wnt/␤-catenin signaling (23).…”

Section: Discussionmentioning

confidence: 99%