Expression of TNF-related apoptosis-inducing ligand in human hepatocellular carcinoma.
TNF-related apoptosis-inducing ligand (TRAIL), as well as Fas ligand, plays a pivotal role in lymphocyte cytotoxicity and the maintenance of immunological homeostasis in various tissues, but its physiological role in immune evasion of cancer cells remains unknown. We have previously shown strong resistance to TRAIL-induced cytotoxicity in human hepatocellular carcinomas (HCCs). The current study investigates the expression of TRAIL in HCCs. We found that three HCC cells, HepG2, Hep3B and Huh7 cells, constitutively express TRAIL mRNA and protein, as detected by reverse transcriptase PCR and Western blotting. Four of 10 human HCC tissues demonstrated positive staining for TRAIL, whereas non-tumor tissues showed little detectable staining. TRAIL expression on tumor cells was detected by flow cytometry and was dramatically induced after the addition of doxorubicin, a chemotherapeutic agent, or cytokine stimulation with TNF-alpha, IL-1beta or IL-18. This expression was induced principally via the NF-kappaB activation pathway, since IkappaB transfection significantly reduced TRAIL expression. In addition, the expressed TRAIL was functional. The TRAIL on HCC cells induced apoptosis in Jurkat cells that are sensitive to TRAIL-mediated apoptosis, and this process was specifically inhibited by recombinant TRAIL-receptors:Fc which binds to TRAIL. In conclusion, TRAIL expressed on the surface of HCC cells by cytokines or cytostatic drugs might contribute to an alternative mechanism that enables tumors to evade immune surveillance by inducing apoptosis of activated human lymphocytes.
Shiraki
Katsuya
K
First Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan. katsuyas@clin.medic.mie-u.ac.jp
Yamanaka
Takenari
T
Inoue
Hidekazu
H
Kawakita
Tomoyuki
T
Enokimura
Naoyuki
N
Okano
Hiroshi
H
Sugimoto
Kazushi
K
Murata
Kazumoto
K
Nakano
Takeshi
T
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D016328:NF-kappa B / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D019014:fas Receptor
D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D004317:Doxorubicin