miR-558 Reduces the Damage of HBE Cells Exposed to Cigarette Smoke Extract by Targeting TNFRSF1A and Inactivating TAK1/MAPK/NF-κB Pathway.

BACKGROUND

Chronic obstructive pulmonary disease (COPD) is a chronic smoking-related lung disease associated with higher mortality and morbidity. Herein, we attempted to investigate the function of miR-558/TNF Receptor Superfamily Member 1A (TNFRSF1A) in the progression of COPD.

METHODS

GEO database was applied to filtrate the differentially expressed mRNAs and miRNAs. KEGG enrichment was used to select the meaningful pathway related to the differentially expressed genes. TargetScan was used to predict the upstream regulator of TNFRSF1A, which was further affirmed by dual luciferase assay. HBE cells were stimulated by 20 μg/mL cigarette smoke extract (CSE) to mimic the COPD . The activity, apoptosis and inflammatory factors of HBE cells were evaluated by biological experiments. The levels of proteins related to TAK1/MAPK/NF-κB pathway were measured by Western blot.

RESULTS

TNFRSF1A is found to be highly expressed in COPD samples and enriched in TNF signaling pathway through bioinformatics analysis. miR-558 was verified as an upstream regulator of TNFRSF1A and negatively regulated TNFRSF1A expression. Up-regulation of miR-558 alleviated CSE-induced damage on HBE cells. The alleviative effect of miR-558 mimic on CSE-induced damage was suppressed by TNFRSF1A overexpression. The elevated expression of -TAK1p-p38 MAPK/p-NF-κB P65 in CSE condition was suppressed by miR-558 up-regulation. However, the results were reversed by TNFRSF1A overexpression. TAK1 inhibitor blocked the activation of TAK1/MAPK/NF-κB pathway, which was consistent with the results from miR-558 up-regulation.

CONCLUSIONS

Up-regulation of miR-558 relieved the damage of HBE cells-triggered by CSE via reducing TNFRSF1A and inactivating TAK1/MAPK/NF-κB pathway, affording novel molecules for COPD treatment.