Identification of transforming growth factor-beta-regulated microRNAs and the microRNA-targetomes in primary lung fibroblasts

Ong, Jennie; Timens, Wim; Rajendran, Vijayanand; Algra, Arjan; Spira, Avrum; Lenburg, Marc E.; Campbell, Joshua D.; Berge, Maarten van den; Postma, Dirkje S.; Berg, Anke van den; Kluiver, Joost; Brandsma, Corry‐Anke

doi:10.1371/journal.pone.0183815

Cited by 38 publications

(49 citation statements)

References 41 publications

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“…Because TGF-β1, a well-known stimulator of EMT, induces the transition of epithelial cells into myofibroblasts, contributing to tissue remodeling and the pathogenesis of CRSwNP [15, 17], the induction of miR-21 by TGF-β1 suggests that miR-21 may have a potential role in the pathogenesis of CRSwNP. The related literature [15, 17, 34, 44] was consistent with our findings.…”

Section: Discussion/conclusionsupporting

confidence: 93%

“…3c, d). In previous studies, miR-21 expression was increased in fibrotic disease and rapidly inducible by TGF-β1 [34, 48, 49]. We then examined expression changes of miR-21 in PHNECs following TGF-β1 treatment.…”

Section: Resultsmentioning

confidence: 95%

“…miR-21 has previously been shown to be induced by an increased level of TGF-β1 during smooth muscle cell development [49]. Soon afterwards, studies revealed that the enhanced expression of miR-21 is involved in the progression of lung fibrosis, and TGF-β1 plays an important role in mediating the increased miR-21 expression [34, 44]. Because TGF-β1, a well-known stimulator of EMT, induces the transition of epithelial cells into myofibroblasts, contributing to tissue remodeling and the pathogenesis of CRSwNP [15, 17], the induction of miR-21 by TGF-β1 suggests that miR-21 may have a potential role in the pathogenesis of CRSwNP.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…Zhong et al [33] provided the first in vitro evidence that miR-21 played a vital role in renal fibrosis in response to TGF-β. Ong et al [34] demonstrated that TGF-β1 induced miR-21 expression in tissue repair and remodeling of lung diseases such as chronic obstructive pulmonary disease. Liu et al [37] demonstrated that miR-21 was required for TGF-β-induced fibrogenic EMT in hepatocytes.…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…miR‑21 is widely expressed and has been found to be increased in organs and tissues which have suffered fibrogenesis or remodeling, including the heart [32], kidney [33], lung [34], asthmatic airways [35, 36], liver [37, 38], skin [39-41], and tumor tissue [42, 43]. Studies revealed that enhanced miR-21 expression is involved in the progression of lung fibrosis, and TGF-β1 plays an important role in mediating increased miR-21 expression [34, 44]. However, there are no studies investigating the expression changes in miR-21 and the relationship between miR-21 and TGF-β1 in EMT of CRSwNP in particular.…”

Section: Introductionmentioning

confidence: 99%

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TGF-β1 Induces Epithelial-Mesenchymal Transition of Chronic Sinusitis with Nasal Polyps through MicroRNA-21

Zhu

et al. 2019

Int Arch Allergy Immunol

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Objectives: To characterize the epithelial-mesenchymal transition (EMT) in chronic rhinosinusitis with nasal polyps (CRSwNP) and to investigate the mechanism by which microRNA-21 (miR-21) regulates EMT in CRSwNP. Method: (1) Tissue experiments: Mucosa tissues were collected from 13 patients with CRSwNP and 12 patients with CRS without nasal polyps (CRSsNP), as well as 11 patients without CRS (controls). Protein localization and quantification were achieved by immunofluorescence staining and Western blotting, involving the epithelial marker protein E-cadherin and the mesenchymal marker proteins α-smooth muscle actin (α-SMA), fibronectin, and vimentin. Quantitative RT-PCR was used to detect the relative expression levels of miR-21 and TGF-β1 mRNAs. (2) Cellular experiments: Primary human nasal epithelial cells (PHNECs) treated with TGF-β1, or TGF-β1 with miR-21 inhibitor, or miR-21 mimics alone were observed for morphology changes under a phase-contrast microscope. The expression levels of epithelial/mesenchymal marker proteins were determined as aforementioned. PTEN and phosphorylated Akt were detected by Western blotting. Results: (1) Tissue experiments: Compared with the CRSsNP and control groups, the expression of E-cadherin was downregulated in the CRSwNP group, whereas the expression of TGF-β1, α-SMA, fibronectin, and vimentin was upregulated. The expression levels of miR-21 and TGF-β1 mRNAs in CRSwNP were significantly higher than those in CRSsNP and controls. (2) Cellular experiments: TGF-β1 induced EMT-like transformation in PHNECs, featured by changes in cell morphology and upregulation of mesenchymal proteins and miR-21. The miR-21 inhibitor, as well as the Akt-specific inhibitor, suppressed TGF-β1-induced EMT. Mechanically, downregulation of miR-21 resulted in increased PTEN and decreased Akt phosphorylation. Furthermore, overexpression of miR-21 had the opposite effects. Conclusions: Our findings suggest that the TGF-β1-miR-21-PTEN-Akt axis may contribute to the pathogenesis of CRSwNP. miR-21 might be a reliable target for treating nasal polyp genesis through EMT suppression. Moreover, miR-21 inhibitors could be a novel class of antipolyp drug that modulates PTEN expression and Akt activation. In addition, further investigation regarding the reason underlying miR-21 overexpression in CRSwNP could provide a molecular target for novel treatment strategies for nasal polyposis.

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Section: Discussion/conclusionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 95%

Section: Discussion/conclusionmentioning

confidence: 99%

Section: Discussion/conclusionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

TGF-β1 Induces Epithelial-Mesenchymal Transition of Chronic Sinusitis with Nasal Polyps through MicroRNA-21

Zhu

et al. 2019

Int Arch Allergy Immunol

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Protective effect of bicyclol against pulmonary fibrosis via regulation of microRNA‐455‐3p in rats

Zhou

Chai

2019

J of Cellular Biochemistry

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Idiopathic pulmonary fibrosis (IPF), a chronic, progressive and irreversible disease, needs long‐term treatment. Bicyclol was found to play a great role in pulmonary fibrosis, and the present study is to explore how bicyclol affects IPF with the involvement of microRNA‐455‐3p (miR‐455‐3p) and Bax. Bleomycin (BLM) was used to induce the IPF model in Sprague‐Dawley rats to detect the expression of miR‐455‐3p, Bax, and B‐cell lymphoma factor 2 (Bcl‐2). Moreover, to further investigate the mechanisms of bicyclol, the BLM‐induced fibrotic cell model was used after the lung epithelial cells HPAEpiC received miR‐455‐3p knockout treatment. The rats were then treated with vehicle and bicyclol, respectively. The apoptosis of fibrotic cells and Bax/Bcl‐2 were identified. Inhibition function of bicyclol was optimal at a dose of 150 mg/kg. Bicyclol inhibited cell apoptosis and reduced Bax/Bcl‐2 expression in rats. miR‐455‐3p could potentially bind to Bax gene. Bicyclol reduced the levels of methylenedioxyamphetamine, superoxide dismutase, and glutathione in rat lung tissue, inhibited the apoptosis of rats with IPF and upregulated miR‐455‐3p expression. In vitro studies showed that bicyclol significantly promoted miR‐455‐3p expression in HPAEpiC fibrosis. Bicyclol inhibited fibrosis‐induced apoptosis of HPAEpiC in alveolar epithelial cells through promoting miR‐455‐3p, which inhibited Bax expression in IPF. Bicyclol may suppress the apoptosis of alveolar epithelial cells by upregulating miR‐455‐3p. This study laid a theoretical foundation for further understanding of IPF and searching for new molecular therapeutic targets.

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Critical role for iron accumulation in the pathogenesis of fibrotic lung disease

Ali

Kim

Brown

et al. 2020

The Journal of Pathology

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Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1 + macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF.

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Identification of transforming growth factor-beta-regulated microRNAs and the microRNA-targetomes in primary lung fibroblasts

Cited by 38 publications

References 41 publications

TGF-β1 Induces Epithelial-Mesenchymal Transition of Chronic Sinusitis with Nasal Polyps through MicroRNA-21

TGF-β1 Induces Epithelial-Mesenchymal Transition of Chronic Sinusitis with Nasal Polyps through MicroRNA-21

Protective effect of bicyclol against pulmonary fibrosis via regulation of microRNA‐455‐3p in rats

Critical role for iron accumulation in the pathogenesis of fibrotic lung disease

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