title: FOXO1 inhibits the invasion and metastasis of hepatocellular carcinoma by reversing ZEB2-induced epithelial-mesenchymal transition.
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.
authors.affiliation: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Tianxiu
authors.initials: T
authors.lastname: Dong
authors.affiliation: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Yaodong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: An
authors.affiliation: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Jiuwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Haichao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Yang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014183:Transplantation, Heterologous; D051879:Twist-Related Protein 1 / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2 / Q000235:genetics / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; C508960:TGFB1 protein, human; C103173:TWIST1 protein, human; D053773:Transforming Growth Factor beta1; D051879:Twist-Related Protein 1; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: FOXO1; TGF-β; ZEB2; epithelial-mesenchymal transition; hepatocellular carcinoma