Coexpression of Oct4 and Nanog Enhances Malignancy in Lung Adenocarcinoma by Inducing Cancer Stem Cell–Like Properties and Epithelial–Mesenchymal Transdifferentiation

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. ©2010 AACR .