期刊
CLINICAL CANCER RESEARCH
卷 25, 期 17, 页码 5364-5375出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-3900
关键词
-
类别
资金
- National Research Foundation of Korea [NRF-2017R1A2B2002327, NRF-2017M2A2A702019560, NRF-2018R1A5A2025286]
- Korean government (Ministry of Science and ICT)
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 IR-induced 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 IkB alpha resulted in increased expressions of Twist, IL-1 beta, 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, IkB alpha-NF kappa B signaling activation by Hsp27, which resulted in the facilitation of Twist, IL1 beta, 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据