Not Only Hypoxia- but Radiation-Induced Epithelial-Mesenchymal Transition Is Modulated by Hypoxia-Inducible Factor 1 in A549 Lung Cancer Cells.
Not Only Hypoxia- but Radiation-Induced Epithelial-Mesenchymal Transition Is Modulated by Hypoxia-Inducible Factor 1 in A549 Lung Cancer Cells.
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DOI：
10.14712/fb2021067020062
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发表时间：
2021
期刊：
影响因子：
0.6
通讯作者：
M. Sato;K. Hirose;K. Ichise;H. Yoshino;T. Harada;Y. Hatayama;H. Kawaguchi;M. Tanaka;I. Fujioka;Y. Takai;M. Aoki
中科院分区：
文献类型：
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作者：
M. Sato;K. Hirose;K. Ichise;H. Yoshino;T. Harada;Y. Hatayama;H. Kawaguchi;M. Tanaka;I. Fujioka;Y. Takai;M. Aoki
缺氧通过上皮-间质转化（EMT）导致癌症的治疗后转移和复发。放射治疗本身也可能有助于获得EMT表型。尽管对低氧或辐射刺激驱动的EMT进行了广泛的研究，但表征这些EMT事件的分子机制仍不清楚。因此，我们的目的是评估缺氧诱导的EMT（Hypo-EMT）和辐射诱导的EMT（R-EMT）之间的分子途径的差异。进一步研究了HIF-1α抑制剂（LW 6）对Hypo-EMT和R-EMT细胞的治疗作用。肺腺癌细胞系A549细胞在缺氧和辐射条件下获得了增强的伤口愈合活性。在缺氧和辐射条件下，E-钙粘蛋白的定位从细胞膜改变到细胞质。值得注意的是，波形蛋白的表达水平，一个主要的EMT标志物，在辐射的细胞，而在缺氧条件下下降。重要的是，LW 6显著阻断了低EMT细胞和R-EMT细胞中EMT相关的恶性表型，同时E-钙粘蛋白重新定位到细胞膜上。此外，LW 6偏转应力响应信号，JNK，激活持续缺氧条件下，和JNK的阻断受损EMT表型。总之，这项工作证明了Hypo-EMT和R-EMT的分子事件，并强调HIF-1α不仅是Hypo-EMT的治疗靶点，也是R-EMT的治疗靶点。
Hypoxia leads to post-treatment metastasis and recurrences of cancer via the epithelial-mesenchymal transition (EMT). Radiotherapy itself may also contribute to the acquisition of EMT phenotypes. Despite extensive studies on the EMT driven by either hypoxia or radiation stimuli, the molecular mechanisms characterizing these EMT events remain unclear. Thus, we aimed to evaluate the differences in the molecular pathways between hypoxia-induced EMT (Hypo-EMT) and radiation-induced EMT (R-EMT). Further, we investigated the therapeutic effects of HIF-1α inhibitor (LW6) on Hypo-EMT and R-EMT cells. A549 cells, lung adenocarcinoma cell line, acquired enhanced wound-healing activity under both hypoxia and irradiation. Localization of E-cadherin was altered from the cell membrane to the cytoplasm in both hypoxia and irradiated conditions. Of note, the expression levels of vimentin, one of the major EMT markers, was enhanced in irradiated cells, while it decreased under hypoxia condition. Importantly, LW6 significantly blocked EMT-related malignant phenotypes in both Hypo-EMT cells and R-EMT cells with concomitant re-location of E-cadherin onto the cell membrane. Moreover, LW6 deflected stress responsive signalling, JNK, activated sustainably under hypoxic condition, and the blockage of JNK impaired EMT phenotypes. Together, this work demonstrated the molecular events underlying Hypo-EMT and R-EMT, and highlighted HIF-1α as a therapeutic target not only in Hypo- EMT, but also in R-EMT.