CD44 is functionally crucial for driving lung cancer stem cells metastasis through Wnt/β-catenin-FoxM1-Twist signaling

A novel paradigm in tumor biology suggests that non-small cell lung cancer (NSCLC) metastasis is driven by lung cancer stem cell-like cells (LCSCs), but the underlying mechanisms remain unclear. Here, we aim to investigate biological function of CD44 in regulating metastatic trait of LCSCs and its underlying mechanisms. In this study, we found that CD133⁺CD44⁺ cells which were derived from primary lung adenocarcinoma (LAC) possessed cancer stem cell-like features. Furthermore, CD44 was demonstrated functionally crucial to drive metastatic potential of CD133⁺CD44⁺ LCSCs by in vitro and in vivo experiments. In patient cohorts, high level of CD44 predicted increased probability of metastasis. Significantly, microarray revealed that FoxM1 and key proteins of Wnt/β-catenin pathway were up-regulated in CD133⁺CD44⁺ LCSCs compared with those in CD133⁺CD44⁻ cells. Then, we demonstrated that CD44 promoted metastatic activity in CD133⁺CD44⁺ LCSCs through Wnt/β-catenin pathway and FoxM1 was the downstream target of Wnt/β-catenin pathway. Meanwhile, our findings indicated that FoxM1 promoted metastatic activity in CD133⁺CD44⁺ LCSCs by inducing EMT and Twist was a direct transcriptional target of FoxM1. Collectively, CD44, both a functional biomarker and therapeutic target, promoted CD133⁺CD44⁺ LCSCs metastasis by Wnt/β-catenin-FoxM1-Twist signaling. This study provided support for the missing link between EMT and CSCs surface-marker and supplied a promising approach for elimination of LCSCs by targeting CD44-Wnt/β-catenin-FoxM1-Twist signaling. © 2015 Wiley Periodicals, Inc.

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