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

Authors

  • Hong Li,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Chao Ge,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Fangyu Zhao,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Mingxia Yan,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Chen Hu,

    1. Department of General Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
    Search for more papers by this author
  • Deshui Jia,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Hua Tian,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Miaoxin Zhu,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Taoyang Chen,

    1. Qi Dong Liver Cancer Institute, Qi Dong, Jiangsu Province, China
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Guoping Jiang,

    1. Department of General Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Haiyang Xie,

    1. Department of General Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Ying Cui,

    1. Cancer Institute of Guangxi, Nanning, China
    Search for more papers by this author
    • These authors contributed equally to this work.

  • Jianren Gu,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Hong Tu,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Xianghuo He,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Ming Yao,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Yongzhong Liu,

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    Search for more papers by this author
  • Jinjun Li

    Corresponding author
    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
    • State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, No.25/Ln 2200, Xie Tu Road, Shanghai 200032, China
    Search for more papers by this author
    • fax: 86-21-64432140

Errata

This article is corrected by:

  1. Errata: Corrections: 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 Volume 54, Issue 6, 2280, Article first published online: 30 November 2011

  • Potential conflict of interest: Nothing to report.

  • This work was supported, in part, by grants from the National Key Sci-Tech Special Project of China (grant 2008ZX10002-022), the National Key Program for Basic Research of China (973) (2009CB521803), the Program Of Shanghai Subject Chief Scientist (A) (09XD1403600), Shanghai Science and Technology Developing Program (07DJ14006), and Shanghai Natural Science Foundation (08ZR1418300).

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. Conclusion: 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. (HEPATOLOGY 2011 54:910–919;)

Ancillary