Long non‑coding RNA TUG1 accelerates abnormal growth of airway smooth muscle cells in asthma by targeting the miR‑138‑5p/E2F3 axis

Abstract

Asthma is a chronic airway inflammatory disease. The present study aimed to explore the effect of the long non-coding RNA taurine-upregulated gene 1 (TUG1) on the viability and migration of airway smooth muscle cells (ASMCs) in asthma. Rat asthma models were constructed with ovalbumin sensitization and challenge and the level of serum immunoglobulin E (IgE) and the rates of inspiratory and expiratory resistance were measured. Reverse transcription-quantitative PCR was also performed to determine the expression levels of TUG1. Platelet-derived growth factor-BB (PDGF-BB)-treated ASMCs were then used as a cell model of asthma. The viability and migratory abilities of ASMCs were analysed with the MTT and Transwell assays. Additionally, a dual-luciferase reporter assay was used to confirm the relationship between TUG1 and microRNA (miR)-138-5p and between transcription factor E2F3 and miR-138-5p. The expression of TUG1, level of serum IgE, inspiratory resistance and expiratory resistance were clearly increased in the rat asthma model in comparison with controls. Knockdown of TUG1 the viability and migration of PDGF-BB-induced ASMCs and reduced the inspiratory and expiratory resistances. In addition, TUG1 functioned as a bait of miR-138-5p, and miR-138-5p modulated E2F3 expression. Knockdown of E2F3 hindered the abnormal growth of ASMCs. Moreover, miR-138-5p inhibition or E2F3 overexpression reversed the inhibitory effects of TUG1 knockdown on viability and migration of PDGF-BB-induced ASMCs. The TUG1/miR-138-5p/E2F3 regulatory axis appeared to play a critical role in accelerating the viability and migration of ASMCs and may therefore have a role in asthma.

Noncoding RNAs in asthmatic airway smooth muscle cells

“…In addition, TUG1 was found to promote airway remodelling and mucus production in asthmatic mice and the TUG1–miR-181b–high mobility group box protein 1 axis was confirmed to work in mouse ASMCs [ 100 ]. Moreover, TUG1 expression was found to be increased in the airway tissue of asthmatic rats and TUG1 inhibition attenuated the viability and migration of the PDGF-BB-induced ASMCs [ 101 ]. The binding relationships between TUG1 and miR-138-5p and between E2F3 and miR-138-5p were confirmed in ASMCs [ 101 ].…”

“…Moreover, TUG1 expression was found to be increased in the airway tissue of asthmatic rats and TUG1 inhibition attenuated the viability and migration of the PDGF-BB-induced ASMCs [ 101 ]. The binding relationships between TUG1 and miR-138-5p and between E2F3 and miR-138-5p were confirmed in ASMCs [ 101 ]. In other words, the TUG1–miR-138-5p–E2F3 regulatory axis was critical to the acceleration of viability and migration of ASMCs [ 101 ].…”

“…The binding relationships between TUG1 and miR-138-5p and between E2F3 and miR-138-5p were confirmed in ASMCs [ 101 ]. In other words, the TUG1–miR-138-5p–E2F3 regulatory axis was critical to the acceleration of viability and migration of ASMCs [ 101 ]. Similarly, TUG1 level was also increased in asthmatic patients and PDGF-BB-stimulated human ASMCs; TUG1 promoted PDGF-BB-induced ASMC proliferation and migration via competitively adsorbing miR-216a-3p, directly targeting the miR-216a-3p-SMURF2 axis [ 102 ].…”

Unlocking the secrets of long non-coding RNAs in asthma

“…However, by sponging, TUG1 inhibits this function and activates the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling pathway and promotes airway remodelling 58. Two recent studies confirmed the involvement of TUG1 in ASMC proliferation in human asthma, by impacting on the miR216a-SMURF2 axis and the miR-138–E2F3 axis 59 60…”

The Novel Regulatory Role of the lncRNA–miRNA–mRNA Axis in Chronic Inflammatory Airway Diseases

“…For example, lncRNA growth arrest-specific transcript 5 (GAS5), lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), and lncRNA PVT1 can act as “sponges” of miR-10a, miR-9-5p, and miR-29c-3p, respectively, and are involved in the biological processes of ASMC proliferation, migration, apoptosis and inflammation in asthmatic patients ( Zhang et al, 2018b ; Wei et al, 2020 ; Wang et al, 2021d ). TUG1, serving as the molecular sponge of miR-138-5p, miR-590-5p, miR-216a-3p, and miR-181b, has been confirmed to be involved in ASMC proliferation and migration in human asthma by modulating E2F transcription factor 3 (E2F3), fibroblast growth factor 1 (FGF1), Smurf2 and HMGB1, respectively ( Lin et al, 2019a ; Huang et al, 2021 ; Wang and Chen, 2021 ; Zhou et al, 2021 ). Similarly, the lncRNA Malat1 also contains multiple binding sites to miRNAs and sponges miR-150 ( Lin et al, 2019b ) and miR-133a ( Yang and Wang, 2021 ) in addition to the aforementioned miR-155 ( Liang and Tang, 2020 ), thereby regulating PDGF-BB-stimulated ASMC proliferation and migration.…”