FOXO1 inhibits the invasion and metastasis of hepatocellular carcinoma by reversing ZEB2-induced epithelial-mesenchymal transition

Abstract

// Tianxiu Dong 1 , Yu Zhang 1 , Yaodong Chen 1 , Pengfei Liu 2 , Tingting An 1 , Jiuwei Zhang 1 , Haichao Yang 1 , Wenjing Zhu 1 , Xiuhua Yang 1 1 Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China 2 Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China Correspondence to: Xiuhua Yang, email: xhyang2016@163.com Keywords: FOXO1, hepatocellular carcinoma, epithelial-mesenchymal transition, ZEB2, TGF-β Received: March 24, 2016     Accepted: November 02, 2016     Published: December 03, 2016 ABSTRACT The epithelial-to-mesenchymal transition (EMT) program is critical for epithelial cell cancer progression and fibrotic diseases. FOXO1 influences a broad range of physiological and pathological processes. However, the mechanism by which FOXO1 inhibits EMT is not fully understood. In this study, we demonstrated that FOXO1 overexpression inhibited cell motility and invasiveness in vitro and inhibited lung metastasis in vivo. In addition, we found that FOXO1 couldreverse the EMT program. FOXO1 silencing by siRNA in hepatocellular carcinoma (HCC) cell lines enhanced the expression of mesenchymal markers and decreased the expression of the epithelial markers. Consistent with these findings, FOXO1 overexpression exerted opposite effects. Furthermore, we found that FOXO1 levels were inversely correlated with the levels of EMT inducers, including Snail, Slug, ZEB1, ZEB2 and Twist1 in HCC cells. Co-immunoprecipitation and immunohistochemistry assays revealed that an interaction between FOXO1 and ZEB2. A dual-luciferase reporter assay and a ChIP assay further demonstrated that FOXO1 binds to the ZEB2 promoter. Together, these findings suggest that FOXO1 overexpression or ZEB2 inhibition might be potential therapeutic strategies for treating HCC.