Induction of MiR-21 by Stereotactic Body Radiotherapy Contributes to the Pulmonary Fibrotic Response.
Induction of MiR-21 by Stereotactic Body Radiotherapy Contributes to the Pulmonary Fibrotic Response.
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DOI：
10.1371/journal.pone.0154942
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Cha HJ
中科院分区：
文献类型：
--
作者：
Kwon OS;Kim KT;Lee E;Kim M;Choi SH;Li H;Fornace AJ Jr;Cho JH;Lee YS;Lee JS;Lee YJ;Cha HJ
放射性肺纤维化是肺癌放射治疗对正常组织最严重的影响，仍然是肺癌患者更广泛应用放射治疗的主要技术障碍。本研究描述了使用图像引导的照射系统在小鼠中模拟立体定向体部放射治疗（SBRT），以检查放射损伤后慢性纤维化反应的分子特征。损伤肺组织的microRNA（miR）阵列分析鉴定了一组miR，其表达在损伤肺组织中显著增加。特别是，miR-21的表达在放射损伤部位增加，同时胶原沉积。尽管通过其特异性抑制剂anti-miR-21抑制miR-21仅轻微影响肺内皮细胞中的内皮-间充质转化（EndMT），但这种抑制显著减少肺成纤维细胞中的胶原合成。此外，miR-21的异位表达足以促进肺成纤维细胞的纤维化反应，增强Smad 2磷酸化，同时Smad 7下调。这些发现表明，诱导miR-21表达是通过增强TGF-β信号传导在损伤部位的间充质细胞中观察到的纤维化反应的原因。在损伤区域局部靶向miR-21可能在减轻辐射诱导的肺纤维化方面具有潜在的治疗效用。
Radiation-induced lung fibrosis, the most serious effect of lung cancer radiotherapy on normal tissue, remains a major technical obstacle to the broader application of radiotherapy to patients with lung cancer. This study describes the use of an image-guided irradiation system in mice mimicking stereotactic body radiotherapy (SBRT) to examine the molecular features of chronic fibrotic response after radiation injury. MicroRNA (miR) array analysis of injured pulmonary tissue identified a set of miRs whose expression was significantly increased in damaged lung tissue. In particular, miR-21 expression was increased at the radiation injury site, concurrent with collagen deposition. Although the inhibition of miR-21 by its specific inhibitor anti-miR-21 only marginally affected endothelial-mesenchymal transition (EndMT) in lung endothelial cells, this inhibition significantly reduced collagen synthesis in lung fibroblasts. Furthermore, ectopic expression of miR-21 was sufficient to promote a fibrotic response in lung fibroblasts, enhancing Smad2 phosphorylation concurrent with Smad7 downregulation. These findings indicate that the induction of miR-21 expression is responsible for fibrotic responses observed in mesenchymal cells at the injury site through the potentiation of TGF-β signaling. Local targeting of miR-21 at the injured area could have potential therapeutic utility in mitigating radiation-induced lung fibrosis.