c-FLIP expression in colorectal carcinomas: association with Fas/FasL expression and prognostic implications.
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.
Korkolopoulou
P
P
Department of Pathology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Saetta
A A
AA
Levidou
G
G
Gigelou
F
F
Lazaris
A
A
Thymara
I
I
Scliri
M
M
Bousboukea
K
K
Michalopoulos
N V
NV
Apostolikas
N
N
Konstantinidou
A
A
Tzivras
M
M
Patsouris
E
E
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*
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