MiR-21 modulates human airway smooth muscle cell proliferation and migration in asthma through regulation of PTEN expression

Liu, Yun; Yang, Kunzheng; Shi, Hongyang; Xu, Jing; Zhang, Dexin; Wu, Yuanyuan; Zhou, Shanshan; Sun, Xuegang

doi:10.3109/01902148.2015.1090501

Cited by 49 publications

(43 citation statements)

References 36 publications

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“…Both C3 and C4 showed eleven genes with identical dysregulation and similar fold change magnitude (Supplemental Table E9). Supplemental Figure E2 illustrates the expression of 5 genes common to both clusters that have been previously linked to airway biology and asthma: TNFAIP3 (18–20); MIR21 (21, 22); HLA-DQA1 (23, 24); IL1RAP (25); and CCL18 (26–28). …”

Section: Resultsmentioning

confidence: 99%

Characterisation of asthma subgroups associated with circulating YKL-40 levels

et al. 2017

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The chitinase-like protein YKL-40 mediates airway inflammation, and serum levels are associated with asthma severity. However, asthma phenotypes associated with YKL-40 levels have not been precisely defined. We conducted an unsupervised cluster analysis of asthma patients treated at the Yale Center for Asthma and Airways Disease (YCAAD, n=156) to identify subgroups according to YKL-40 level. The resulting YKL-40 clusters were cross-validated in cohorts from the Severe Asthma Research Program (SARP) (n=167) and the New York University Bellevue Asthma Repository (NYUBAR) (n=341). A sputum transcriptome analysis revealed molecular pathways associated with YKL-40 subgroups. Four YKL-40 clusters (C1-4) were identified. C3 and C4 had high serum YKL-40 levels compared to C1 and C2. C3 was associated with earlier onset and longer duration of disease, severe airflow obstruction and near-fatal asthma exacerbations. C4 had the highest serum YKL-40 levels, adult onset, and less airflow obstruction but frequent exacerbations. An airway transcriptome analysis in C3 and C4 showed activation of non-Type 2 inflammatory pathways. Elevated serum YKL-40 levels were associated with two distinct clinical asthma phenotypes: one with irreversible airway obstruction and another with severe exacerbations. The YKL-40 clusters are potentially useful for identification of individuals with severe or exacerbation-prone asthma.

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Section: Resultsmentioning

confidence: 99%

Characterisation of asthma subgroups associated with circulating YKL-40 levels

et al. 2017

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“…8 The promoting role of miR-21 on human airway SMC proliferation and migration has been previously investigated. 21 Interestingly, miR-21-5p was found to regulate the expression of apoptosis-related factors, inhibiting cellular apoptosis. 22 The inhibition of miR-21-5p reduced proliferation and invasion, but elevated apoptosis of colon adenocarcinoma cells and esophageal squamous cell carcinoma cells.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells‐derived exosomal microRNA‐21‐5p downregulates PDCD4 and ameliorates erectile dysfunction in a rat model of diabetes mellitus

Huo

Zhang

et al. 2020

FASEB j.

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Erectile dysfunction (ED) is a common comorbidity in males with diabetes mellitus (DM), whose pathogenesis might be induced by dysregulation of corpus cavernosum smooth muscle cells (CCSMCs). Gene Expression Omnibus repository‐based analysis identified the differentially expressed PDCD4 in DM rats. PDCD4 has also been determined as a putative gene under the regulatory control of microRNA‐21‐5p (miR‐21‐5p). This study aimed to further determine the functional role of miR‐21‐5p in CCSMCs in a rat model of diabetes mellitus‐induced erectile dysfunction (DMED). CCSMCs were isolated from penile cavernous tissue and cultured in high glucose (HG) medium. The expression of miR‐21‐5p and/or PDCD4 was altered in CCSMCs, as directly or indirectly measured by CCK‐8 assay, flow cytometry, and TUNEL assays. Furthermore, exosomes were isolated from mesenchymal stem cells (MSCs) transfected with miR‐21‐5p mimic or miR‐21‐5p inhibitor and co‐cultured with CCSMCs. DMED rats were injected with lentivirus carrying PDCD4/siRNA‐PDCD4 plasmids, or exosomes from MSCs containing miR‐21‐5p‐agomir to explore their roles in vivo. The experimental data validated that PDCD4 was upregulated in cavernous tissue of DMED rats. miR‐21‐5p targeted and inhibited PDCD4. miR‐21‐5p was enriched in MSC‐exosomes. Moreover, PDCD4 downregulation, miR‐21‐5p elevation or MSC‐derived exosomal miR‐21‐5p reduced apoptosis and enhanced proliferation of CCSMCs cultured in HG medium. PDCD4 silencing or miR‐21‐5p‐containing MSC‐exosomes improved erectile function and smooth muscle density in DMED rats. Collectively, our findings suggested that MSC‐derived exosomal miR‐21‐5p suppressed PDCD4 expression and ED in rats with DM.

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“…Notably, microRNA 21 (miR‐21) has been found to be the most highly upregulated miRNA in the lungs of asthmatic mice (T. X. Lu, Munitz, & Rothenberg, ). Further study has indicated that the overexpression of miR‐21 promotes human ASMC proliferation by targeting phosphatase and tensin homolog deleted on chromosome ten (PTEN; Y. Liu et al, ). However, the specific mechanisms underlying the upregulation of miR‐21 in ASMCs and the mechanisms by which miR‐21 induces ASMC proliferation are still unclear.…”

Section: Introductionmentioning

confidence: 99%

Activation of peroxisome proliferation–activated receptor‐γ inhibits transforming growth factor‐β1‐induced airway smooth muscle cell proliferation by suppressing Smad–miR‐21 signaling

Liu

Pan

Zhai

et al. 2018

Journal Cellular Physiology

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The aims of the current study were to examine the signaling mechanisms for transforming growth factor-β1 (TGF-β1)-induced rat airway smooth muscle cell (ASMC) proliferation and to determine the effect of activation of peroxisome proliferation-activated receptor-γ (PPAR-γ) on TGF-β1-induced rat ASMC proliferation and its underlying mechanisms. TGF-β1 upregulated microRNA 21 (miR-21) expression by activating Smad2/3, and this in turn downregulated forkhead box O1 (FOXO1) mRNA expression. In addition, TGF-β1-Smad-miR-21 signaling also downregulated phosphatase and tensin homolog deleted on chromosome ten (PTEN) expression and thus de-repressed the PI3K-Akt pathway. Depletion of PTEN reduced the nuclear FOXO1 protein level without affecting its mRNA level. Inhibition of the PI3K-Akt pathway or proteasome function reversed PTEN knockdown-induced nuclear FOXO1 protein reduction. Our study further showed that loss of FOXO1 increased cyclin D1 expression, leading to rat ASMC proliferation. Preincubation of rat ASMCs with pioglitazone, a PPAR-γ activator, blocked TGF-β1-induced activation of Smad2/3 and its downstream targets changes of miR-21, PTEN, Akt, FOXO1, and cyclin D1, resulting in the inhibition of rat ASMC proliferation. Our study suggests that the activation of PPAR-γ inhibits rat ASMC proliferation by suppressing Smad-miR-21 signaling and therefore has a potential value in the prevention and treatment of asthma by negatively modulating airway remodeling.

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MiR-21 modulates human airway smooth muscle cell proliferation and migration in asthma through regulation of PTEN expression

Abstract: This study provides the first in vitro evidence that overexpression of miR-21 in HASM cells can trigger cell proliferation and migration, and the effects of miR-21 depend on the level of PTEN.

Cited by 49 publications

References 36 publications

Characterisation of asthma subgroups associated with circulating YKL-40 levels

Characterisation of asthma subgroups associated with circulating YKL-40 levels

Mesenchymal stem cells‐derived exosomal microRNA‐21‐5p downregulates PDCD4 and ameliorates erectile dysfunction in a rat model of diabetes mellitus

Activation of peroxisome proliferation–activated receptor‐γ inhibits transforming growth factor‐β1‐induced airway smooth muscle cell proliferation by suppressing Smad–miR‐21 signaling

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