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Jan 03, 2017;8 (1): 1703-1713.

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

Tianxiu Dong, Yu Zhang, Yaodong Chen, Pengfei Liu, Tingting An, Jiuwei Zhang, Haichao Yang, Wenjing Zhu, Xiuhua Yang
Author Information
  1. Tianxiu Dong: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
  2. Yu Zhang: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
  3. Yaodong Chen: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
  4. Pengfei Liu: Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
  5. Tingting An: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
  6. Jiuwei Zhang: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
  7. Haichao Yang: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
  8. Wenjing Zhu: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
  9. Xiuhua Yang: Department of Abdominal Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China.
PMID: 27924058 DOI: 10.18632/oncotarget.13786

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.

Keywords

FOXO1 TGF-β ZEB2 epithelial-mesenchymal transition hepatocellular carcinoma

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MeSH Term

Animals
Carcinoma, Hepatocellular
Cell Line, Tumor
Cell Movement
DNA-Binding Proteins
Epithelial-Mesenchymal Transition
Forkhead Box Protein O1
Humans
Liver Neoplasms
Lung Neoplasms
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Metastasis
Neoplasm Transplantation
Nuclear Proteins
Promoter Regions, Genetic
RNA Interference
RNA, Small Interfering
Snail Family Transcription Factors
Transforming Growth Factor beta1
Transplantation, Heterologous
Twist-Related Protein 1
Zinc Finger E-box Binding Homeobox 2
Zinc Finger E-box-Binding Homeobox 1

Chemicals

DNA-Binding Proteins
FOXO1 protein, human
Forkhead Box Protein O1
Nuclear Proteins
RNA, Small Interfering
Snail Family Transcription Factors
TGFB1 protein, human
TWIST1 protein, human
Transforming Growth Factor beta1
Twist-Related Protein 1
ZEB1 protein, human
ZEB2 protein, human
Zinc Finger E-box Binding Homeobox 2
Zinc Finger E-box-Binding Homeobox 1
Journal Article

Word Cloud

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