title: Hypoxia-inducible factor 1 alpha-activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin β1 signaling in human hepatocellular carcinoma.
abstract: Angiopoietin-like protein 4 (ANGPTL4) plays complex and often contradictory roles in vascular biology and tumor metastasis, but little is known about its function in hepatocellular carcinoma (HCC) metastasis. In the present study, we showed that hypoxia-inducible factor 1α (HIF-1α) directly up-regulates ANGPTL4, and its stableness positively correlates with ANGPTL4 expression in HCC tissue. Overexpression of ANGPTL4 significantly increased HCC cell transendothelial migration in vitro and intrahepatic and distal pulmonary metastasis in vivo, whereas silencing ANGPTL4 expression or treatment with a neutralizing antibody specific for ANGPTL4 protein resulted in a reduced transendothelial migration. We also found that serum ANGPTL4 is higher in HCC patients, compared to healthy control, and correlates with intrahepatic metastasis and histological grade. Further, secreted ANGPTL4 promotes transendothelial migration and metastasis of HCC cells in vitro and in vivo through the up-regulation of vascular cell adhesion molecule-1 (VCAM-1) of human umbilical vein endothelial cells and the activation of the VCAM-1/integrin β1 axis.
  
  
  CONCLUSIONS
  ANGPTL4 is a target gene of HIF-1α and acts as an important regulator in the metastasis of HCC. Serum ANGPTL4 correlates with tumor progression and metastasis and might be used to indicate prognosis in HCC patients.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Chao
authors.initials: C
authors.lastname: Ge
authors.forename: Fangyu
authors.initials: F
authors.lastname: Zhao
authors.forename: Mingxia
authors.initials: M
authors.lastname: Yan
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.forename: Deshui
authors.initials: D
authors.lastname: Jia
authors.forename: Hua
authors.initials: H
authors.lastname: Tian
authors.forename: Miaoxin
authors.initials: M
authors.lastname: Zhu
authors.forename: Taoyang
authors.initials: T
authors.lastname: Chen
authors.forename: Guoping
authors.initials: G
authors.lastname: Jiang
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.forename: Ying
authors.initials: Y
authors.lastname: Cui
authors.forename: Jianren
authors.initials: J
authors.lastname: Gu
authors.forename: Hong
authors.initials: H
authors.lastname: Tu
authors.forename: Xianghuo
authors.initials: X
authors.lastname: He
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Yongzhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Jinjun
authors.initials: J
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D019012:Integrin beta1 / Q000502:physiology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology
chemical_list: C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019012:Integrin beta1; D019010:Vascular Cell Adhesion Molecule-1