The Hsp27-mediated IkBα-NFκB signaling axis promotes radiation-induced lung fibrosis

Jee Youn Kim, Seulgi Jeon, Young Jo Yoo, Hee Jin, Hee Yeon Won, Kyeonghee Yoon, Eun Sook Hwang, Yoon Jin Lee, Younghwa Na, Jaeho Cho, Yun Sil Lee

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Purpose: Lung fibrosis is a major side effect experienced by patients after lung cancer radiotherapy. However, effective protection strategies and underlying treatment targets remain unclear. In an effort to improve clinical outcomes, pharmacologic treatment of fibrosis is becoming increasingly popular; however, no ideal therapeutic strategy is yet available. Experimental Design: We used a mouse model to irradiate high focal (90 or 75 Gy) to 3-mm volume of the left lung. Lung tissues of mice were subjected to microarray, mRNA expression, and immunohistochemical analysis. Correlations of radiation (IR)-induced epithelial-mesenchymal transition (EMT) were validated in lung cell lines using appropriate treatments to activate or inhibit selected pathways. Results: The expression of Hsp27 was increased during IRinduced lung fibrosis in a mouse model. Inhibition of functional Hsp27 using shRNA and a synthetic small molecule inhibitor (J2) in lung cells alleviated IR-mediated EMT. The activation of NFkB pathways via direct interaction between Hsp27 and IkBα resulted in increased expressions of Twist, IL-1β, and IL-6 and facilitated IR-mediated EMT, which was identified as an underlying mechanism of Hsp27-mediated fibrosis after IR. J2 also inhibited IR-induced lung fibrosis in an orthotopic lung cancer model, and IR-induced lung fibrotic tissues from patients showed higher expression of Hsp27 than unirradiated lungs. Conclusions: Collectively, IkBa-NFkB signaling activation by Hsp27, which resulted in the facilitation of Twist, IL1b, and IL6 expression, is involved in the EMT process that is tightly connected to the development of IR-induced lung fibrosis. Our findings also suggest that inhibition of Hsp27 has the potential to become a valuable therapeutic strategy for IR-induced lung fibrosis.

Original languageEnglish
Pages (from-to)5364-5375
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number17
DOIs
Publication statusPublished - 2019 Sep 1

Bibliographical note

Funding Information:
This work was supported by grants from the National Research Foundation of Korea, (NRF-2017R1A2B2002327, NRF-2017M2A2A702019560,

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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