Oxysterol-binding Protein-related Protein 8 (ORP8) Increases Sensitivity of Hepatocellular Carcinoma Cells to Fas-Mediated Apoptosis

• Published in: The Journal of biological chemistry 2015-04, Vol.290 (14), p.8876-8887
• Main Authors: Zhong, Wenbin, Qin, Shengying, Zhu, Biying, Pu, Miaoshui, Liu, Fupei, Wang, Lin, Ye, Guilin, Yi, Qing, Yan, Daoguang
• Format: Article
• Language: English
• Subjects: Apoptosis; Apoptosis - physiology; Base Sequence; Carcinoma, Hepatocellular - pathology; Cell Biology; Cell Line, Tumor; DNA Primers; Endoplasmic Reticulum Stress (ER Stress); Fas; fas Receptor - physiology; Flow Cytometry; Humans; Liver Cancer; Liver Neoplasms - pathology; MicroRNA (miRNA); ORP8; Polymerase Chain Reaction; Protein Translocation; Receptors, Steroid - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.610188

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. Background: The mechanism of HCC resistant to Fas-mediated apoptosis is not clearly understood. Results: ORP8 triggered HCC cell apoptosis via relocation of cytoplasmic Fas to the cell plasma membrane and FasL up-regulation. Conclusion: ORP8 increases sensitivity of HCC cells to Fas-mediated apoptosis. Significance: New insights reveal that ORP8 may serve as a potential target for HCC therapy.