Role of interleukin-18 and its receptor in hepatocellular carcinoma associated with hepatitis C virus infection.
Interleukin (IL)-18 is a proinflammatory cytokine that is up-regulated in patients with hepatitis C virus (HCV) infection, which is the most common underlying disease in hepatocellular carcinoma (HCC). The purpose of our study was to investigate the role of IL-18 in HCC associated with HCV infection. Sixty-five patients with HCC and HCV infections who received curative surgical resections were examined in our study. The expression of the IL-18 receptor was investigated in HCC tissues obtained from these patients and in 2 HCC cell lines. Nuclear factor (NF)-kappaB activity and the expression of Bcl-xL and xIAP mRNA were tested in the cell lines using recombinant human (rh) IL-18. The IL-18 receptor was expressed in both the HCC tissues and the cell lines. NF-kappaB activation and the expression of Bcl-xL and xIAP mRNA were increased by rhIL-18. Moreover, rhIL-18 suppressed the apoptosis of HCC cells which was induced by etoposide in vitro. The overall survival rate (55.4%) was significantly worse in the IL-18 receptor-positive patients than in the IL-18 receptor-negative patients (p = 0.015). In a Cox multivariate analysis, the expression of the IL-18 receptor was found to be a significant predictor of a poor outcome in HCC patients. The expression of the IL-18 receptor and an antiapoptotic mechanism involving NF-kappaB activation in HCC cells may be implicated in a poor patient outcome.
Asakawa
Masami
M
First Department of Surgery, University of Yamanashi, Yamanashi, Japan. asakawa.m@nifty.com
Kono
Hiroshi
H
Amemiya
Hidetake
H
Matsuda
Masanori
M
Suzuki
Tetsuya
T
Maki
Akira
A
Fujii
Hideki
H
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D016174:Hepacivirus / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000378:metabolism* / Q000821:virology; D006801:Humans; D020382:Interleukin-18 / Q000502:physiology*; D053727:Interleukin-18 Receptor alpha Subunit; D008113:Liver Neoplasms / Q000378:metabolism* / Q000821:virology; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000502:physiology*; D053724:Receptors, Interleukin-18; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C494811:BCL2L1 protein, human; D016207:Cytokines; C508572:IL18R1 protein, human; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D016328:NF-kappa B; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053724:Receptors, Interleukin-18; D011994:Recombinant Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D005047:Etoposide