MiRNA-155-5p inhibits epithelium-to-mesenchymal transition (EMT) by targeting GSK-3β during radiation-induced pulmonary fibrosis

Arch Biochem Biophys. 2021 Jan 15:697:108699. doi: 10.1016/j.abb.2020.108699. Epub 2020 Nov 28.

Abstract

Radiation-induced pulmonary fibrosis (RIPF) is a major lung complication in using radiotherapy to treat thoracic diseases. MicroRNAs (miRNAs) are reported to be the therapeutic targets for many diseases. However, the miRNAs involved in the pathogenesis of RIPF are rarely studied as potential therapeutic targets. Alveolar epithelial cells participate in RIPF formation by undergoing epithelial-mesenchymal transition (EMT). Here we demonstrated the critical role of miR-155-5p in radiation-induced EMT and RIPF. Using the previously established EMT cell model, we found that miR-155-5p was significantly down-regulated through high-throughput sequencing. Irradiation could decrease the expression of miR-155-5p in intro and in vivo, and it was inversely correlated to RIPF formation. Ectopic miR-155-5p expression inhibited radiation-induced-EMT in vitro and in vivo. Knockdown of glycogen synthase kinase-3β (GSK-3β), the functional target of miR-155-5p, reversed the induction of EMT and enhanced the phosphorylation of p65, a subunit of NF-κB, which were mediated by the down-regulation of miR-155-5p. Moreover, our finding demonstrated that ectopic miR-155-5p expression alleviated RIPF in mice by the GSK-3β/NF-κB pathway. Thus, radiation downregulates miR-155-5p in alveolar epithelial cells that induces EMT, which contributes to RIPF using GSK-3β/NF-κB pathway. Our observation provides further understanding on the regulation of RIPF and identifies potential therapeutic targets.

Keywords: EMT; GSK-3β; NF-κB; Radiation-induced pulmonary fibrosis; miRNA; miRNA-155–5p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Epithelial-Mesenchymal Transition / genetics
  • Epithelial-Mesenchymal Transition / radiation effects*
  • Gene Knockdown Techniques
  • Glycogen Synthase Kinase 3 beta / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • NF-kappa B / metabolism
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology*
  • Radiation Injuries, Experimental / genetics*
  • Radiation Injuries, Experimental / metabolism
  • Radiation Injuries, Experimental / pathology*

Substances

  • MicroRNAs
  • Mirn155 microRNA, mouse
  • NF-kappa B
  • Glycogen Synthase Kinase 3 beta