Growth differentiation factor 15 induces growth and metastasis of human liver cancer stem-like cells via AKT/GSK-3β/β-catenin signaling

// Qiong Xu 1, 2, * , Hai-Xu Xu 1, * , Jin-Ping Li 2 , Song Wang 2 , Zheng Fu 1, 2 , Jing Jia 2 , Li Wang 1, 2 , Zhi-Feng Zhu 2 , Rong Lu 1, 2 , Zhi Yao 1 1 Department of Immunology, Tianjin Medical University, Tianjin, China 2 Tianjin Kangzhe Pharmaceutical Company, Ltd., Tianjin, China * These authors contributed equally to this work Correspondence to: Zhi Yao, email: yaozhi@tijmu.edu.cn Rong Lu, email: lu_rong@vip.sina.com Keywords: cancer stem cells, hepatocellular carcinoma, GDF15, metastasis, tumorigenesis Received: November 25, 2016      Accepted: January 27, 2017      Published: February 09, 2017 ABSTRACT Cancer stem cells in liver cancer are thought to be responsible for tumor recurrence and metastasis. However, the factors that mediate this mechanism have yet to be completely elucidated. In this study, we isolated CD13 + CD44 + sphere cells (SCs) derived from liver cancer tissues and SK-Hep-1 cells, which possessed cancer stem cell-like properties. Through cytokine array analysis, growth differentiation factor 15 (GDF15) was significantly increased in SCs. Clinical data showed GDF15 was overexpressed in liver cancer tissues and was positively related to pathological grading. GDF15 knockdown significantly inhibited the growth and metastasis of SCs through AKT/GSK-3β/β-catenin pathway suppression. Moreover, a PI3K inhibitor LY294002 inhibited AKT/GSK-3β/β-catenin pathway activated by GDF15 and attenuated GDF15-induced proliferation, colony formation and invasion of SCs. Conclusion: Our studies suggest that CD13 + CD44 + SCs may represent a subset of LCSCs. GDF15 promotes the growth and metastasis of SCs by activating AKT/GSK-3β/β-catenin signaling pathway. Promisingly, GDF15 could be considered as a potential therapeutic target in liver cancer.