HDAC8-inhibitor PCI-34051-induced exosomes inhibit human bronchial smooth muscle cell proliferation via miR-381-3p mediated TGFB3

The present study aimed to investigate the effects of PCI-34051-induced human bronchial epithelial cells (HBECs)-derived exosomes (PCI-Exo) on human bronchial smooth muscle cells (HBSMCs) and the key exosomal miRNAs involved in this process. Blank exosomes (Exo) and PCI-Exo were extracted from HBECs treated with PBS and PCI-34051, respectively. RNA-sequencing was performed to uncover the miRNA expression profile affected by PCI-Exo. The MTT, flow cytometry and TUNEL assays were performed to reveal the effect of PCI-34051 and PCI-Exo on the proliferation and apoptosis of HBSMCs. Western blotting and qRT-PCR were used for detecting protein and mRNA expression. A total of 25 exosomal miRNAs consisted of 17 down-regulated and eight up regulated miRNAs were differentially expressed among PCI-Exo and Exo. Target genes of the exosomal miRNAs were mainly associated with signal transduction, cell adhesion, microRNAs in cancer, and ECM receptor interaction. miR-381-3p was identified as the most significant upregulated differential miRNA in PCI-Exo after qRT-PCR validation and could be transferred to HBSMCs by PCI-Exo. PCI-Exo treatment inhibited the proliferation but induced the apoptosis of HBSMCs. TGF beta 3 was identified as a target gene of miR-381-3p which could directly bind to the 3'UTR of TGF beta 3 mRNA. After transfecting the miR-381-3p mimic into HBSMCs, the proliferation inhibition and apoptosis rate of HBSMCs was significantly increased, and siTGF beta 3 transfection showed similar effects. Moreover, miR-381-3p overexpression could not only decrease the expression of alpha-SMA, FN1 and collagen I but also increase that of E-cadherin in HBSMCs. Our findings suggested that PCI-Exo could hinder the proliferation and obviously induce the apoptosis of HBSMCs, and its mechanisms might partly be attributable to the reduction of TGF beta 3 level by up-regulating exosomal miR-381-3p expression. These results may be vital for the treatment of lung related-diseases, especially asthma.

Automated summary

The study aimed to investigate the effects of PCI-34051-induced exosomes from human bronchial epithelial cells on human bronchial smooth muscle cells and the key exosomal miRNAs involved in this process. It was found that PCI-Exo inhibited HBSMCs proliferation and induced apoptosis, with miR-381-3p being the most significant differential miRNA transferred by PCI-Exo. The mechanisms behind these effects involve the reduction of TGF beta 3 level by up-regulating exosomal miR-381-3p expression, which may have important implications for the treatment of lung-related diseases, especially asthma.