Coexpression of Oct4 and Nanog Enhances Malignancy in Lung Adenocarcinoma by Inducing Cancer Stem Cell-Like Properties and Epithelial-Mesenchymal Transdifferentiation
Coexpression of Oct4 and Nanog Enhances Malignancy in Lung Adenocarcinoma by Inducing Cancer Stem Cell-Like Properties and Epithelial-Mesenchymal Transdifferentiation
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DOI：
10.1158/0008-5472.can-10-2638
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Wu, Cheng-Wen
中科院分区：
文献类型：
--
作者：
Chiou, Shih-Hwa;Wang, Mong-Lien;Wu, Cheng-Wen
上皮-间质转化（Epithelial-mesenchymal transition，EMT）是肿瘤侵袭和转移的关键过程，与肿瘤细胞的干性有关。虽然Oct 4和Nanog是干细胞自我更新所必需的同源盒转录因子，并在几种癌症中表达，但Oct 4/Nanog信号传导在肿瘤发生中的作用仍然难以捉摸。微阵列和实时定量PCR分析显示，Oct 4和Nanog在肺腺癌（LAC）中的表达平行升高。Oct 4和Nanog在拉克中的异位表达增加了CD 133表达亚群和球体形成的百分比，增强了耐药性，并促进了EMT。Oct 4和Nanog的异位表达激活了Slug，增强了LAC的肿瘤启动能力。同时，Oct 4和Nanog的双敲除抑制了Slug的表达，逆转了EMT过程，阻断了肿瘤的发生和转移能力，大大提高了移植免疫功能低下小鼠的平均生存时间。免疫组化分析显示Oct 4、Nanog和Slug在高级别LAC中均有表达，Oct 4/Nanog/Slug三重阳性提示LAC患者预后较差。我们的研究结果支持Oct 4/Nanog信号转导控制上皮-间充质转分化，调节肿瘤起始能力，并促进LAC转移的观点。Cancer Res; 70（24）; 10433-44.（C）2010年AACR。
Epithelial-mesenchymal transition (EMT), a critical process of cancer invasion and metastasis, is associated with stemness property of cancer cells. Though Oct4 and Nanog are homebox transcription factors essential to the self-renewal of stem cells and are expressed in several cancers, the role of Oct4/Nanog signaling in tumorigenesis is still elusive. Here microarray and quantitative real-time PCR analysis showed a parallel, elevated expression of Oct4 and Nanog in lung adenocarcinoma (LAC). Ectopic expressions of Oct4 and Nanog in LACs increased the percentage of CD133-expressing subpopulation and sphere formation, enhanced drug resistance, and promoted EMT. Ectopic expressions of Oct4 and Nanog activated Slug and enhanced the tumor-initiating capability of LAC. Furthermore, double knockdown of Oct4 and Nanog suppressed the expression of Slug, reversed the EMT process, blocked the tumorigenic and metastatic ability, and greatly improved the mean survival time of transplanted immunocompromised mice. The immunohistochemical analysis demonstrated that expressions of Oct4, Nanog, and Slug were present in high-grade LAC, and triple positivity of Oct4/Nanog/Slug indicated a worse prognostic value of LAC patients. Our results support the notion that the Oct4/Nanog signaling controls epithelial-mesenchymal transdifferentiation, regulates tumor-initiating ability, and promotes metastasis of LAC. Cancer Res; 70(24); 10433-44. (C)2010 AACR.