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.
Highlights
The mechanism of hepatocellular carcinoma (HCC) resistant to Fas-mediated apoptosis is not clearly understood
Because aberrant elevation of the cholesterol level is associated with various types of cancers [16], a total of 67 clinical HCC samples were analyzed for oxysterol-binding protein-related protein 8 (ORP8) expression for both mRNA and protein expression by qRTPCR and Western blot
These results indicated that mechanisms other than weak Fas expression are involved in hepatoma cell apoptosis resistance
Summary
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. Human hepatoma (HCC) has been reported to be strongly resistant to Fas-mediated apoptosis. 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. 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. Our previous study indicated that ORP8 decreases cholesterol efflux in macrophages by suppressing ABCA1 expression, implying that it may play a role in the development
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