title: c-FLIP expression in colorectal carcinomas: association with Fas/FasL expression and prognostic implications.
abstract: OBJECTIVE
  Disruption of apoptotic cell death has been implicated in tumour aggressiveness in colonic carcinogenesis. The Fas-Fas ligand (FasL) system is involved in the execution of apoptosis induced by the immune system. c-FLIP protein constitutes an inhibitor of Fas and other (TRAIL) death receptor-mediated apoptosis. The aim of this study was to investigate the simultaneous expression of Fas, FasL and c-FLIP in relation to standard clinicopathological parameters and patients' outcome in colorectal cancer.
  
  
  RESULTS
  Levels of Fas, FasL and c-FLIP protein expression were quantified immunohistochemically in paraffin-embedded tissues from 90 patients. Immunopositivity was detected for Fas, FasL and c-FLIP in 71%, 35.5% and 68.8% of cases, respectively. Concurrent expression of Fas/FasL was seen in 28 samples (31%), of which 24 (85.7%) also displayed c-FLIP positivity (P = 0.04). c-FLIP overexpression (> 10%) tended to prevail marginally in higher stage tumours (P = 0.09). Additionally, FasL and c-FLIP adversely affected survival on both univariate (P = 0.001 and P = 0.0024, respectively) and multivariate analysis [hazard ratio (HR) 3.491, P = 0.005 and HR 2.960, P = 0.036, respectively].
  
  
  CONCLUSIONS
  The frequent expression and coexpression of Fas, FasL and c-FLIP in colorectal carcinoma implicates c-FLIP as an inhibitor of the Fas-FasL-induced death pathway in these tumours. Moreover, c-FLIP conveys independent prognostic information in the presence of classical prognosticators.
authors.affiliation: Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Korkolopoulou
authors.forename: A A
authors.initials: AA
authors.lastname: Saetta
authors.forename: G
authors.initials: G
authors.lastname: Levidou
authors.forename: F
authors.initials: F
authors.lastname: Gigelou
authors.forename: A
authors.initials: A
authors.lastname: Lazaris
authors.forename: I
authors.initials: I
authors.lastname: Thymara
authors.forename: M
authors.initials: M
authors.lastname: Scliri
authors.forename: K
authors.initials: K
authors.lastname: Bousboukea
authors.forename: N V
authors.initials: NV
authors.lastname: Michalopoulos
authors.forename: N
authors.initials: N
authors.lastname: Apostolikas
authors.forename: A
authors.initials: A
authors.lastname: Konstantinidou
authors.forename: M
authors.initials: M
authors.lastname: Tzivras
authors.forename: E
authors.initials: E
authors.lastname: Patsouris
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D053222:Fas Ligand Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019014:fas Receptor