title: Prognostic significance of death-associated protein-kinase expression in hepatocellular carcinomas.
abstract: 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.
authors.affiliation: First Department of Surgery, Nara Medical University, 840 Shijo-cho, Kashihara city, Nara 634-8522, Japan. hmatsu@nmu-gw.naramed-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Nagao
authors.forename: Sanehito
authors.initials: S
authors.lastname: Ogawa
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Kanehiro
authors.forename: Michiyoshi
authors.initials: M
authors.lastname: Hisanaga
authors.forename: Saiho
authors.initials: S
authors.lastname: Ko
authors.forename: Naoya
authors.initials: N
authors.lastname: Ikeda
authors.forename: Hisao
authors.initials: H
authors.lastname: Fujii
authors.forename: Fumikazu
authors.initials: F
authors.lastname: Koyama
authors.forename: Tomohide
authors.initials: T
authors.lastname: Mukogawa
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Nakajima
mesh_terms: 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
chemical_list: 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