Radiation promotes invasiveness of non-small-cell lung cancer cells through granulocyte-colony-stimulating factor
Radiation promotes invasiveness of non-small-cell lung cancer cells through granulocyte-colony-stimulating factor
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DOI：
10.1038/onc.2014.466
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发表时间：
2015-10-16
期刊：
影响因子：
8
通讯作者：
Lee, S-J
中科院分区：
文献类型：
--
作者：
Cui, Y-H;Suh, Y.;Lee, S-J
尽管电离辐射 (IR) 被广泛用作肺癌的标准治疗方法，但许多证据表明，IR 反而会促进癌症恶性化。然而，其辐射诱发癌症进展的分子机制仍不清楚。在此，我们报告暴露于分次放射（每天 2 Gy，持续 3 天）会诱导粒细胞集落刺激因子 (G-CSF) 的分泌，该因子常用于癌症治疗以改善中性粒细胞减少症。有趣的是，辐射诱导的 G-CSF 通过触发非小细胞肺癌细胞 (NSCLC) 的上皮间质细胞转变 (EMT) 来促进迁移和侵袭特性。通过辐射，G-CSF 被 β-连环蛋白/TCF4 复合物上调转录，该复合物作为转录因子与 G-CSF 启动子区域结合。重要的是，辐射通过激活 PI3K/AKT（磷脂酰肌醇 3-激酶/AKT）增加了 β-连环蛋白的稳定性，从而上调了 G-CSF 的表达。放射诱导的 G-CSF 被 G-CSFR 识别并转导其细胞内信号 JAK/STAT3（Janus 激酶/信号转导子和转录激活子），从而触发 NSCLC 中的 EMT 程序。总而言之，我们的研究结果表明，由于 G-CSF 对癌症进展的影响，应重新考虑在癌症治疗中应用 G-CSF 来改善中性粒细胞减少症，并且 G-CSF 可能成为减轻 NSCLC 放疗有害作用的新治疗靶点。
Despite ionizing radiation (IR) is being widely used as a standard treatment for lung cancer, many evidences suggest that IR paradoxically promotes cancer malignancy. However, its molecular mechanisms underlying radiation-induced cancer progression remain obscure. Here, we report that exposure to fractionated radiation (2 Gy per day for 3 days) induces the secretion of granulocyte-colony-stimulating factor (G-CSF) that has been commonly used in cancer therapies to ameliorate neutropenia. Intriguingly, radiation-induced G-CSF promoted the migratory and invasive properties by triggering the epithelial-mesenchymal cell transition (EMT) in non-small-cell lung cancer cells (NSCLCs). By irradiation, G-CSF was upregulated transcriptionally by beta-catenin/TCF4 complex that binds to the promoter region of G-CSF as a transcription factor. Importantly, irradiation increased the stability of beta-catenin through the activation of PI3K/AKT (phosphatidylinositol 3-kinase/AKT), thereby upregulating the expression of G-CSF. Radiation-induced G-CSF is recognized by G-CSFR and transduced its intracellular signaling JAK/STAT3 (Janus kinase/ signal transducers and activators of transcription), thereby triggering EMT program in NSCLCs. Taken together, our findings suggest that the application of G-CSF in cancer therapies to ameliorate neutropenia should be reconsidered owing to its effect on cancer progression, and G-CSF could be a novel therapeutic target to mitigate the harmful effect of radiotherapy for the treatment of NSCLC.