NRF2/miR-140 signaling confers radioprotection to human lung fibroblasts
NRF2/miR-140 signaling confers radioprotection to human lung fibroblasts
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DOI：
10.1016/j.canlet.2015.08.011
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发表时间：
2015-12-01
期刊：
影响因子：
9.7
通讯作者：
Zhou, Qun
中科院分区：
文献类型：
--
作者：
Duru, Nadire;Gernapudi, Ramkishore;Zhou, Qun
接受放射治疗的乳腺癌和肺癌患者通常会产生严重的副作用，包括辐射引起的肺损伤和继发性癌症。NRF 2通路的激活是一种众所周知的保护细胞免受辐射诱导的氧化应激的机制，但其在辐射诱导的肺损伤中的作用尚不清楚。使用人肺成纤维细胞（HLF），我们发现电离辐射（IR）通过抑制KEAP 1功能，促进NRF 2的核积累，并激活关键的辐射防护机制，从而导致NRF 2的BRCA 1依赖性激活。我们发现NRF 2直接与miR-140启动子结合，并在IR处理后增加其表达。功能获得和丧失研究进一步显示了miR-140在照射后调节肺成纤维细胞自我更新的能力，这是一种有助于调节DNA修复的潜在机制。我们使用野生型和Nrf 2（KO）小鼠的原代肺成纤维细胞培养物验证了我们的体外发现。使用这些模型，我们发现IR诱导照射后肺组织中Brca 1、Nrf 2和miR-140的过表达。这些数据揭示了一种新的辐射防护机制，其中IR促进HLF中NRF 2核转位和随后的miR-140转录激活。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Breast and lung cancer patients who are treated with radiotherapy often have severe side effects, including radiation-induced lung damage and secondary cancers. Activation of the NRF2 pathway is a well-known mechanism that protects cells against radiation induced oxidative stress, but its role in radiation-induced lung damage is not well understood. Using human lung fibroblasts (HLFs) we found that ionizing radiation (IR) leads to BRCA1-dependent activation of NRF2 through the inhibition of KEAP1 function, promoting the nuclear accumulation of NRF2, and activating critical radioprotective mechanisms. We discovered that NRF2 directly binds to the miR-140 promoter and increases its expression in response to IR treatment. Gain and loss of function studies further showed the ability of miR-140 to regulate lung fibroblast self-renewal upon irradiation, a potential mechanism to contribute to the regulation of DNA repair. We verified our in vitro findings using primary lung fibroblast cultures from wild type and Nrf2 (KO) mice. Using these models we showed that IR induces overexpression of Brca1, Nrf2 and miR-140 in lung tissue after irradiation. These data reveal a novel radioprotective mechanism in which IR promotes NRF2 nuclear translocation and subsequent activation of miR-140 transcription in HLFs. (C) 2015 Elsevier Ireland Ltd. All rights reserved.