Prognostic significance of death-associated protein-kinase expression in hepatocellular carcinomas.
BACKGROUND
Disorder of programmed cell death (PCD) contributes to the pathogenesis and the progression of various cancers. Death-associated protein-kinase(DAP-kinase) was isolated as a positive mediator of apoptosis induced by IFN-gamma. It has been reported that the loss or reduction of DAP-kinase expression was detected in various human tumor cell lines and resulted from methylation of the DAP-kinase gene.


METHODS
We investigated the expression of DAP-kinase protein by immunohistochemistry and Western-blotting in 43 patients with hepatocellular carcinoma (HCC). Additionally, we examined the methylation status of the DAP-kinase promoter region by methylation-specific polymerase chain reaction.


RESULTS
In DAP-kinase-positive HCC cases(n = 16), serum AFP levels were lower (p = 0.009), tumor differentiation was higher (p = 0.048), histological portal invasion and metastatic foci were less (p = 0.004 and 0.016, respectively), apoptosis of tumor cells was more (p = 0.0009), and the disease-free survival rate and the overall survival rate were higher (p = 0.0057 and 0.0246, respectively), compared with DAP-kinase-negative cases. The status of DAP-kinase protein expression closely correlated with IFN-gamma-receptor and Fas expression (p = 0.038 and p < 0.0001, respectively), but not the methylation of promoter region.


CONCLUSIONS
Hepatoma cells may escape from apoptosis through the loss or reduction of DAP-kinase expression, while the block of IFN-gamma signal transduction as well as the methylation of promoter region may reduce the expression of DAP-kinase protein.
Matsumoto
Hiroshi
H
First Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara city, Nara 634-8522, Japan. hmatsu@nmu-gw.naramed-u.ac.jp
Nagao
Mitsuo
M
Ogawa
Sanehito
S
Kanehiro
Hiromichi
H
Hisanaga
Michiyoshi
M
Ko
Saiho
S
Ikeda
Naoya
N
Fujii
Hisao
H
Koyama
Fumikazu
F
Mukogawa
Tomohide
T
Nakajima
Yoshiyuki
Y
D000368:Aged; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D002454:Cell Differentiation; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D064550:Death-Associated Protein Kinases; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D015993:Life Tables; D008113:Liver Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D017471:Receptors, Interferon / Q000032:analysis; D015398:Signal Transduction; D016019:Survival Analysis; D015996:Survival Rate; D019014:fas Receptor / Q000032:analysis; D000096743:Interferon gamma Receptor
D051017:Apoptosis Regulatory Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004273:DNA, Neoplasm; D064550:Death-Associated Protein Kinases; D009363:Neoplasm Proteins; D017471:Receptors, Interferon; D019014:fas Receptor; D000096743:Interferon gamma Receptor