title: 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.
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and Department of Biotechnology, Jinan University, Guangzhou, 510632, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Zhong
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and Department of Biotechnology, Jinan University, Guangzhou, 510632, China.
authors.forename: Shengying
authors.initials: S
authors.lastname: Qin
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and Department of Biotechnology, Jinan University, Guangzhou, 510632, China.
authors.forename: Biying
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Hepatobiliary Surgery, Guangzhou General Hospital, Guangzhou 510010, China, and.
authors.forename: Miaoshui
authors.initials: M
authors.lastname: Pu
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and Department of Biotechnology, Jinan University, Guangzhou, 510632, China.
authors.forename: Fupei
authors.initials: F
authors.lastname: Liu
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and Department of Biotechnology, Jinan University, Guangzhou, 510632, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and Department of Biotechnology, Jinan University, Guangzhou, 510632, China.
authors.forename: Guilin
authors.initials: G
authors.lastname: Ye
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.affiliation: From the Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and Department of Biotechnology, Jinan University, Guangzhou, 510632, China, tydg@jnu.edu.cn.
authors.forename: Daoguang
authors.initials: D
authors.lastname: Yan
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D016133:Polymerase Chain Reaction; D011987:Receptors, Steroid / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*; D000098825:Oxysterol Binding Proteins
chemical_list: D017931:DNA Primers; D011987:Receptors, Steroid; D019014:fas Receptor; D000098825:Oxysterol Binding Proteins
keywords: Apoptosis; Endoplasmic Reticulum Stress (ER Stress); Fas; Liver Cancer; MicroRNA (miRNA); ORP8; Protein Translocation