title: Cytosolic and nuclear caspase-8 have opposite impact on survival after liver resection for hepatocellular carcinoma.
abstract: BACKGROUND
  An imbalance between proliferation and apoptosis is one of the main features of carcinogenesis. TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis upon binding to the TRAIL death receptors, TRAIL receptor 1 (TRAIL-R1) and TRAIL-R2, whereas binding to TRAIL-R3 and TRAIL-R4 might promote cell survival and proliferation. The anti-tumor activity of TRAIL-R1 and TRAIL-R2 agonists is currently investigated in clinical trials. To gain further insight into the regulation of apoptosis in hepatocellular carcinoma (HCC), we investigated the TRAIL pathway and the regulators of apoptosis caspase-8, Bcl-xL and Mcl-1 in patients with HCC regarding patient survival.
  
  
  METHODS
  We analyzed 157 hepatocellular carcinoma patients who underwent partial liver resection or orthotopic liver transplantation and healthy control liver tissue using immunohistochemistry on tissue microarrays for the expression of TRAIL-R1 to TRAIL-R4, caspase-8, Bcl-xL and Mcl-1. Immunohistochemical data were evaluated for potential associations with clinico-pathological parameters and survival.
  
  
  RESULTS
  Whereas TRAIL-R1 was downregulated in HCC in comparison to normal liver tissue, TRAIL-R2 and -R4 were upregulated in HCC, especially in G2 and G3 tumors. TRAIL-R1 downregulation and upregulation of TRAIL-R2 and TRAIL-R4 correlated with tumor dedifferentiation (G2/G3). TRAIL-R3, Bcl-xL and Mcl-1 showed no differential expression in tumor tissue compared to normal tissue. The expression levels of TRAIL receptors did not correlate with patient survival after partial hepatectomy. Interestingly, in tumor tissue, but not in normal hepatocytes, caspase-8 showed a strong nuclear staining. Low cytosolic and high nuclear staining intensity of caspase-8 significantly correlated with impaired survival after partial hepatectomy, which, for cytosolic caspase-8, was independent from tumor grade.
  
  
  CONCLUSIONS
  Assessment of TRAIL-receptor expression patterns may have therapeutic implications for the use of TRAIL receptor agonists in HCC therapy. Tumor-specific nuclear localisation of caspase-8 in HCC suggests an apoptosis-independent function of caspase-8 and correlates with patient survival.
authors.forename: Ronald
authors.initials: R
authors.lastname: Koschny
authors.forename: Sylvia
authors.initials: S
authors.lastname: Brost
authors.forename: Ulf
authors.initials: U
authors.lastname: Hinz
authors.forename: Jaromir
authors.initials: J
authors.lastname: Sykora
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Batke
authors.forename: Stephan
authors.initials: S
authors.lastname: Singer
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.forename: Henning
authors.initials: H
authors.lastname: Walczak
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of Gastroenterology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. tom.ganten@med.uni-heidelberg.de.
authors.forename: Tom M
authors.initials: TM
authors.lastname: Ganten
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D053181:Caspase 8 / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000601:surgery; D008297:Male; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D021381:Protein Transport; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D053181:Caspase 8