Fractionated Ionizing Radiation Promotes Epithelial-Mesenchymal Transition in Human Esophageal Cancer Cells through PTEN Deficiency-Mediated Akt Activation.
Fractionated Ionizing Radiation Promotes Epithelial-Mesenchymal Transition in Human Esophageal Cancer Cells through PTEN Deficiency-Mediated Akt Activation.
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DOI：
10.1371/journal.pone.0126149
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
He E;Pan F;Li G;Li J
在某些食管癌患者中，放射治疗可能无法预防远处转移，从而导致生存率低。这些患者转移的潜在机制尚未完全确定。在本研究中，我们已经证明电离辐射可以通过下调磷酸酶和张力蛋白同源物（PTEN）以及激活Akt/GSK-3β/Snail信号转导来诱导上皮-间质转化（EMT），伴随着细胞迁移和侵袭的增加。我们建立了一个放射抗性（RR）食管鳞癌细胞系，KYSE-150/RR，通过分割电离辐射（IR）处理，并证实其放射抗性使用克隆形成生存分析。我们发现KYSE-150/RR细胞系具有典型的EMT的形态学和分子特征。与亲本细胞相比，KYSE-150/RR细胞显示IR后集落存活、迁移和侵袭性增加。此外，观察到KYSE-150/RR细胞中的PTEN减少。我们推测过表达的PTEN可以诱导KYSE-150/RR细胞的间质-上皮转化，并恢复IR诱导的细胞迁移增加。从机制上讲，分级IR抑制PTEN的表达，这导致Akt/GSK-3β信号转导的激活，并与EMT中涉及的转录因子Snail蛋白水平升高相关。相应地，用磷脂酰肌醇-3-激酶抑制剂LY 294002处理，在KYSE-150/RR细胞中模拟PTEN过表达效应，进一步表明Akt/GSK-3β/Snail信号传导在通过PTEN介导的效应中的作用。总之，这些结果强烈表明，KYSE-150/RR细胞中的分级IR介导的EMT是通过PTEN依赖性途径，突出了放射治疗对肿瘤细胞的直接促侵袭作用。
In some esophageal cancer patients, radiotherapy may not prevent distant metastasis thus resulting in poor survival. The underlying mechanism of metastasis in these patients is not well established. In this study, we have demonstrated that ionizing radiation may induce epithelial-mesenchymal transition (EMT) accompanied with increased cell migration and invasion, through downregulation of phosphatase and tensin homolog (PTEN), and activation of Akt/GSK-3β/Snail signaling. We developed a radioresistant (RR) esophageal squamous cancer cell line, KYSE-150/RR, by fractionated ionizing radiation (IR) treatment, and confirmed its radioresistance using a clonogenic survival assay. We found that the KYSE-150/RR cell line displayed typical morphological and molecular characteristics of EMT. In comparison to the parental cells, KYSE-150/RR cells showed an increase in post-IR colony survival, migration, and invasiveness. Furthermore, a decrease in PTEN in KYSE-150/RR cells was observed. We postulated that over-expression of PTEN may induce mesenchymal-epithelial transition in KYSE-150/RR cells and restore IR-induced increase of cell migration. Mechanistically, fractionated IR inhibits expression of PTEN, which leads to activation of Akt/GSK-3β signaling and is associated with the elevated levels of Snail protein, a transcription factor involved in EMT. Correspondingly, treatment with LY294002, a phosphatidylinositol-3-kinase inhibitor, mimicked PTEN overexpression effect in KYSE-150/RR cells, further suggesting a role for the Akt/GSK-3β/Snail signaling in effects mediated through PTEN. Together, these results strongly suggest that fractionated IR-mediated EMT in KYSE-150/RR cells is through PTEN-dependent pathways, highlighting a direct proinvasive effect of radiation treatment on tumor cells.
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