The miR-15b-Smurf2-HSP27 axis promotes pulmonary fibrosis

Seulgi Jeon, Hee Jin, Jin Mo Kim, Youmin Hur, Eun Joo Song, Yoon Jin Lee, Younghwa Na, Jaeho Cho, Yun Sil Lee

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background: Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated. Methods: We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used. Results: HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF. Conclusions: Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.

Original languageEnglish
Article number2
JournalJournal of Biomedical Science
Volume30
Issue number1
DOIs
StatePublished - Dec 2023

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation of Korea, (NRF-2018R1A5A2025286, NRF-2020R1A2C3013255, NRF-2020M2D9A2093974, NRF-2020R1I1A1A01070841, NRF-2020M2D9A2093976 and NRF-2022R1A2C3011611), funded by the Korean government (Ministry of Science and ICT).

Publisher Copyright:
© 2023, The Author(s).

Keywords

  • HSP27
  • Phosphorylation
  • Protein degradation
  • Pulmonary fibrosis
  • Smurf2
  • miRNA

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