Expression of TNF-related apoptosis-inducing Ligand receptors and antitumor tumor effects of TNF-related apoptosis-inducing Ligand in human hepatocellular carcinoma.
OBJECTIVE
To investigate the expression of TNF-related apoptosis -inducing Ligand (TRAIL) receptors and antitumor effects of TRAIL in hepatocellular carcinoma (HCC).


METHODS
Expression of TRAIL receptors was determined in 60 HCC tissues, 20 normal liver samples and two HCC cell lines (HepG2 and SMMC-7721). The effects of TRAIL on promoting apoptosis in HCC cell lines were analyzed after the cells were exposed to the recombinant TRAIL protein, as well as transfected with TRAIL-expression construct. In vivo effects of TRAIL on tumor growth were investigated by using nude mice HCC model of hepG2.


RESULTS
Both death receptors were expressed in all HCC tissues and normal hepatic samples. In contrast, 54 HCC tissues did not express DcR1 and 25 did not express DcR2. But both DcR were detectable in all of the normal liver tissues. The expression patterns of DR and DcR in HCC samples (higher DR expression level and lower DcR expression level) were quite different from those in normal tissue. DR5, DR4, and DcR2 expressed in both cell lines, while no DcR1 expression was detected. Recombinant TRAIL alone was found to have a slight activity as it killed a maximum of 15 % of HCC cells within 24 h. Transfection of the TRAIL cDNA failed to induce extensive apoptosis in HCC lines. In vivo administration of TRAIL gene could not inhibit tumor growth in nude mice HCC model. However, chemotherapeutic agents or anticancer cytokines dramatically augmented TRAIL-induced apoptosis in HCC cell lines.


CONCLUSIONS
Loss of DcR (especially DcR1) in HCC may contribute to antitumor effects of TRAIL to HCC.HCC is insensitive towards TRAIL-mediated apoptosis, suggesting that the presence of mediators can inhibit the TRAIL cell-death-inducing pathway in HCC. TRAIL and chemotherapeutic agents or anticancer cytokines combination may be a novel strategy for the treatment of HCC.
Chen
Xiao-Ping
XP
Hepatic Surgery Center, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China. chenxp_53@sina.com
He
Song-Qing
SQ
Wang
Hai-Ping
HP
Zhao
Yong-Zhong
YZ
Zhang
Wan-Guang
WG
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000235:genetics; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D019169:Jurkat Cells; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008819:Mice, Nude; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000502:physiology; D053319:Tumor Necrosis Factor Decoy Receptors
D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D007376:Interleukin-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C505640:Tnfrsf10b protein, mouse; D053319:Tumor Necrosis Factor Decoy Receptors; D004815:Epidermal Growth Factor