Peroxiredoxin 4 suppresses anoikis and augments growth and metastasis of hepatocellular carcinoma cells through the β-catenin/ID2 pathway.

Affiliation

Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, No.17 Lujiang Road, Luyang District, Hefei, 230001, Anhui, People's Republic of China. [Email]

Abstract

OBJECTIVE : Peroxiredoxin 4 (PRDX4) has been reported to play a dual role in the progression of hepatocellular carcinoma (HCC). As yet, however, the underlying molecular mechanism has not been fully elucidated.
METHODS : We examined the effects of PRDX4 on the growth and survival of HCC cells in an anchorage-independent microenvironment. The regulation of β-catenin stability and activity by PRDX4 was investigated.
RESULTS : We found that PRDX4 depletion reduced, and PRDX4 overexpression increased, both anchorage-dependent and anchorage-independent growth of HCC cells. We also found that PRDX4 depletion caused an overproduction of reactive oxygen species (ROS) in HCC cells, especially under suspension conditions. PRDX4 knockdown predisposed HCC cells to anoikis, whereas PRDX4 overexpression induced resistance to anoikis. Subsequent in vivo studies confirmed that PRDX4 deficiency blocks HCC tumor growth and pulmonary metastasis. Mechanistically, we found that RDX4 reduced β-TrCP-mediated β-catenin ubiquitination and enhanced β-catenin protein stability, consequently leading to activation of β-catenin signaling. Silencing of β-catenin impaired PRDX4-mediated anchorage-independent growth and survival, whereas β-catenin overexpression increased the survival and growth of PRDX4-depleted cells under anchorage-independent conditions. Further investigation revealed that the β-catenin downstream gene ID2 is responsible for the oncogenic activity of PRDX4 in HCC cells, promoting anchorage-independent growth and anoikis resistance.
CONCLUSIONS : PRDX4 reduces anoikis and promotes tumorigenesis and metastasis of HCC cells through stabilization of the β-catenin protein and upregulation of ID2. Targeting of PRDX4 may represent a promising strategy to block HCC cell growth and metastasis.

Keywords

Anoikis,Growth,Hepatocellular carcinoma,Metastasis,PRDX4,