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Oxysterol-binding protein-related protein 8 (ORP8) increases sensitivity of hepatocellular carcinoma cells to Fas-mediated apoptosis.

Abstract
Human hepatoma (HCC) has been reported to be strongly resistant to Fas-mediated apoptosis. However, the underlying mechanisms are poorly understood. In this study the function of oxysterol-binding protein-related protein 8 (ORP8) in human hepatoma cells apoptosis was assessed. We found that ORP8 is down-regulated, whereas miR-143, which controls ORP8 expression, is up-regulated in clinical HCC tissues as compared with liver tissue from healthy subjects. ORP8 overexpression triggered apoptosis in primary HCC cells and cell lines, which coincided with a relocation of cytoplasmic Fas to the cell plasma membrane and FasL up-regulation. Co-culture of HepG2 cells or primary HCC cells with Jurkat T-cells or T-cells, respectively, provided further evidence that ORP8 increases HCC cell sensitivity to Fas-mediated apoptosis. ORP8-induced Fas translocation is p53-dependent, and FasL was induced upon ORP8 overexpression via the endoplasmic reticulum stress response. Moreover, ORP8 overexpression and miR-143 inhibition markedly inhibited tumor growth in a HepG2 cell xenograft model. These results indicate that ORP8 induces HCC cell apoptosis through the Fas/FasL pathway. The role of ORP8 in Fas translocation to the plasma membrane and its down-regulation by miR-143 offer a putative mechanistic explanation for HCC resistance to apoptosis. ORP8 may be a potential target for HCC therapy.
AuthorsWenbin Zhong, Shengying Qin, Biying Zhu, Miaoshui Pu, Fupei Liu, Lin Wang, Guilin Ye, Qing Yi, Daoguang Yan
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 14 Pg. 8876-87 (Apr 03 2015) ISSN: 1083-351X [Electronic] United States
PMID25596532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
Chemical References
  • DNA Primers
  • Receptors, Steroid
  • fas Receptor
  • oxysterol binding protein
Topics
  • Apoptosis (physiology)
  • Base Sequence
  • Carcinoma, Hepatocellular (pathology)
  • Cell Line, Tumor
  • DNA Primers
  • Flow Cytometry
  • Humans
  • Liver Neoplasms (pathology)
  • Polymerase Chain Reaction
  • Receptors, Steroid (physiology)
  • fas Receptor (physiology)

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