Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma
Metformin inhibits the radiation-induced invasive phenotype of esophageal squamous cell carcinoma
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DOI：
10.3892/ijo.2016.3676
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发表时间：
2016-11-01
影响因子：
5.2
通讯作者：
Ohta, Tetsuo
中科院分区：
文献类型：
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作者：
Nakayama, Akira;Ninomiya, Itasu;Ohta, Tetsuo
食管癌是最具侵袭性的肿瘤类型之一，因为它具有侵袭性和转移潜力。一些报告已经描述了电离辐射（IR）治疗后增加的侵袭性和上皮间质转化（EMT）之间的关联。据报道，双胍二甲双胍可预防转化生长因子-β（TGF-β）诱导的EMT和癌症增殖。本研究检测了IR是否诱导EMT并促进TE-9食管鳞状细胞癌细胞的侵袭潜力，以及二甲双胍对IR诱导的EMT的影响。红外线照射后TE-9细胞呈梭形，细胞间粘附能力丧失。免疫印迹显示IR诱导间充质标记物（波形蛋白和N-钙粘蛋白）、转录因子（Slug、Snail和Twist）和基质金属蛋白酶的表达。划痕实验和Matrigel侵袭实验显示IR增强TE-9细胞的侵袭能力和迁移能力。IR后低氧相关因子-1 α和TGF-β的表达增加。IR还诱导Smad 2和Smad 3的磷酸化。二甲双胍抑制辐射诱导的EMT样形态学改变，增强TE-9细胞的侵袭和迁移。二甲双胍抑制IR诱导的Smad 2和Smad 3磷酸化。虽然AMP活化蛋白激酶的磷酸化被IR和二甲双胍增强，但雷帕霉素的哺乳动物靶点的磷酸化被IR增强并被二甲双胍抑制。这些结果表明，二甲双胍通过抑制TGF-β-Smad磷酸化途径和部分非Sthad途径抑制IR诱导的EMT。美托洛尔可能有助于预防食管鳞癌的IR诱导的侵袭和转移。
Esophageal cancer is one of the most aggressive tumor types because of its invasiveness and metastatic potential. Several reports have described an association between increased invasiveness after ionizing radiation (IR) treatment and epithelial-to-mesenchymal transition (EMT). The biguanide metformin is reported to prevent transforming growth factor-beta (TGF-beta)-induced EMT and proliferation of cancer. This study examined whether IR induces EMT and promotes the invasive potential of TE-9 esophageal squamous cell carcinoma cells and the effect of metformin on IR-induced EMT. After IR exposure, TE-9 cells showed a spindle-shaped morphology and lost cell-cell adhesion. Immunoblotting showed that IR induced expression of mesenchymal markers (vimentin and N-cadherin), transcription factors (Slug, Snail, and Twist), and matrix metalloproteinases. A scratch wound assay and Matrigel invasion assay showed that IR enhanced the invasive potential and migratory capacity of TE-9 cells. Expression of hypoxia-related factor-1 alpha and TGF-beta was increased after IR. IR also induced phosphorylation of Smad2 and Smad3. Metformin inhibited radiation-induced EMT-like morphological changes, and enhanced invasion and migration of TE-9 cells. Metformin inhibited IR-induced phosphorylation of Smad2 and Smad3. Although phosphorylation of AMP-activated protein kinase was enhanced by IR and metformin, phosphorylation of mammalian target of rapamycin was enhanced by IR and suppressed by metformin. These results indicated that metformin suppressed IR-induced EMT via suppression of the TGF-P-Smad phosphorylation pathway, and a part of the non-Sthad pathway. Metformin might be useful to prevent IR-induced invasion and metastasis of esophageal squamous cell carcinoma.