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

• Published in: Oncotarget Vol. 8; no. 1; pp. 1703 - 1713
• Main Authors: Dong, Tianxiu, Zhang, Yu, Chen, Yaodong, Liu, Pengfei, An, Tingting, Zhang, Jiuwei, Yang, Haichao, Zhu, Wenjing, Yang, Xiuhua
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 03.01.2017
• Subjects: Animals; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Movement; DNA-Binding Proteins - metabolism; Epithelial-Mesenchymal Transition - physiology; Forkhead Box Protein O1 - genetics; Forkhead Box Protein O1 - metabolism; Humans; Liver Neoplasms - pathology; Lung Neoplasms - pathology; Lung Neoplasms - secondary; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Neoplasm Transplantation; Nuclear Proteins - metabolism; Promoter Regions, Genetic - genetics; Research Paper; RNA Interference; RNA, Small Interfering - genetics; Snail Family Transcription Factors - metabolism; Transforming Growth Factor beta1 - metabolism; Transplantation, Heterologous; Twist-Related Protein 1 - metabolism; Zinc Finger E-box Binding Homeobox 2 - genetics; Zinc Finger E-box Binding Homeobox 2 - metabolism; Zinc Finger E-box-Binding Homeobox 1 - metabolism; TGF-β; ZEB2; epithelial-mesenchymal transition; FOXO1; hepatocellular carcinoma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.13786

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.