ERK/GSK3β/Snail signaling mediates radiation-induced alveolar epithelial-to-mesenchymal transition.
ERK/GSK3β/Snail signaling mediates radiation-induced alveolar epithelial-to-mesenchymal transition.
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DOI：
10.1016/j.freeradbiomed.2011.11.024
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发表时间：
2012-03-15
影响因子：
7.4
通讯作者：
Zhao, Weiling
中科院分区：
文献类型：
--
作者：
Nagarajan, Devipriya;Melo, Tahira;Deng, Zhiyong;Almeida, Celine;Zhao, Weiling
关键词：
放射治疗是胸部恶性肿瘤的主要治疗方案之一，但可导致严重的肺部并发症，包括肺炎和纤维化。最近的研究表明，上皮间质转化（EMT）在导致器官纤维化的组织损伤中起重要作用。为了研究放射是否可以诱导肺上皮细胞中的EMT以及了解与这种变化相关的潜在机制，用8戈伊的137 Cs γ射线照射大鼠肺泡II型肺上皮细胞RLE-6 TN。蛋白质印迹和免疫荧光分析显示，辐射后E-钙粘蛋白呈时间依赖性减少，α-SMA和波形蛋白同时增加，这表明上皮细胞获得了间充质样形态。EMT的关键诱导物Snail蛋白水平和核转位在辐射细胞中显著升高。辐射还诱导糖原合成酶激酶-3 β（GSK 3 β）的时间依赖性失活，GSK 3 β是Snail的内源性抑制剂。在照射的RLE-6 TN细胞中观察到ERK 1/2磷酸化的显著增加，而非JNKs或p38。使用siRNA沉默ERK 1/2和MEK/ERK抑制剂U 0126减弱了辐射诱导的RLE-6 TN细胞中GSK 3 β的磷酸化，并改变了Snail、α-SMA和E-cadherin的蛋白水平。用抗氧化剂N-乙酰半胱氨酸预孵育RLE-6 TN细胞，可消除辐射诱导的ERK磷酸化，并改变Snail、E-cadherin和α-SMA的蛋白水平。这些研究结果首次揭示了肺泡II型上皮细胞中辐射诱导的EMT是由ERK/GSK 3 β/Snail通路介导的。
Radiotherapy is one of the major treatment regimes for thoracic malignancies, but can lead to severe lung complications including pneumonitis and fibrosis. Recent studies suggest that epithelial to mesenchymal transition (EMT) plays an important role in tissue injury leading to organ fibrosis. To investigate whether radiation can induce EMT in lung epithelial cells and also understand the potential mechanism(s) associated with this change, rat alveolar type II lung epithelial RLE-6TN cells were irradiated with 8 Gy of 137Cs γ-rays. Western blot and immunofluorescence analyses revealed a time-dependent decrease in E-cadherin with a concomitant increase in α-SMA and vimentin after radiation, suggesting that the epithelial cells acquired mesenchymal-like morphology. Protein levels and nuclear translocation of Snail, the key inducer of EMT, were significantly elevated in the irradiated cells. Radiation also induced a time-dependent inactivation of glycogen synthase kinase-3β (GSK3ß), an endogenous inhibitor of Snail. A marked increase in phosphorylation of ERK1/2, but not JNKs or p38, was observed in irradiated RLE-6TN cells. Silencing ERK1/2 using siRNAs and the MEK/ERK inhibitor U0126 attenuated the radiation-induced phosphorylation of GSK3ß and altered the protein levels of Snail, α-SMA and E-cadherin in RLE-6TN cells. Pre-incubating RLE-6TN cells with N-acetyl cysteine, an antioxidant, abolished the radiation-induced phosphorylation of ERK and altered protein levels of Snail, E-cadherin and α-SMA. These findings reveal, for the first time, that radiation-induced EMT in alveolar type II epithelial cells is mediated by the ERK/GSK3ß/Snail pathway.
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影响因子：
3
作者：
Grgic, Ivica;Duffield, Jeremy S.;Humphreys, Benjamin D.
通讯作者：
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影响因子：
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de Herreros, AG
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