- 作者: Seulgi Jeon, Hee Jin, Jin-Mo Kim, Youmin Hur, Eun Joo Song, Yoon-Jin Lee, Younghwa Na, Jaeho Cho & Yun-Sil Lee
- 作者服務機構: 1.College of Pharmacy, CHA University, 120, Haeryong-ro, Pocheon-si, Gyeonggi-do, 11160, Republic of Korea 2.Department of Manufacturing Pharmacy, Natural Product Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea 3.Department of Radiation Oncology, Yonsei University Health System, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea 4.Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea 5.Inhalation Toxicity Research Group, Korea Institute of Toxicology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea 6.Korea Institute of Radiological and Medical Science, Seoul, 01812, Republic of Korea
- 中文摘要:
- 英文摘要:
Background Heat shock protein 27 (HSP27) is overexpressed during pulmonary fbrosis (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 ortho‑
tropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fbrosis, and
lung tissues from various fbrotic 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 inhibi‑
tor, J2 was also used.
Results HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expres‑
sion of SMAD-specifc 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 identi‑
fed 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 efective when target‑
ing the epithelial to mesenchymal transition (EMT) stage of PF.
Conclusions Our fndings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy
for HSP27 inhibition for overcoming PF - 中文關鍵字:
- 英文關鍵字: HSP27, Phosphorylation, miRNA, Pulmonary fbrosis, Smurf2, Protein degradation