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Unit of Molecular Therapies, Department of Experimental Oncology and Laboratories, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 20133 Milan, Italy
¹ Institute of Medical Statistics and Biometry, Università degli Studi di Milano, Via Vanzetti 5, 20133 Milan, Italy Departments of
² Anatomy Pathology
³ Surgical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 20133 Milan, Italy Departments of
⁴ Pathology
⁵ Gynecological Surgery, S. Chiara Hospital, L.go Medaglie d'Oro, 9 38100 Trento, Italy
⁶ Unit of Medical Statistics and Biometry, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 1 20133 Milan, Italy

(Correspondence should be addressed to S Canevari; Email: silvana.canevari{at}istitutotumori.mi.it)

^* (S Canevari and D Mezzanzanica contributed equally to this work)

The impairment of apoptotic pathways represents an efficient mechanism to promote chemoresistance in cancer cells. We previously showed that in epithelial ovarian cancer (EOC) cells, long isoform of cellular FLICE-inhibitory protein (c-FLIP_L) accounts for apoptosis resistance in a context of functional p53 and resistance could be overcome by c-FLIP_L downmodulation. Here, we studied the association between c-FLIP_L and p53 expressions and their prognostic impact in EOC patients. Tumor tissue from 207 patients diagnosed with primary EOC was analyzed by immunohistochemistry (IHC) for c-FLIP_L and p53 expressions, and multiple correspondence analysis (MCA) was used to evaluate the multivariable pattern of association among patients' clinical–pathological characteristics and biological determinants. IHC revealed c-FLIP_L expression and p53 nuclear accumulation inversely related (P=0.0001; odds ratio=0.29, confidence interval (CI)=0.15–0.055). MCA indicated that p53 accumulation was associated to clinical–pathological variables, while c-FLIP_L expression contributed to the overall association pattern independently from other's clinical characteristics and complementary to p53. Kaplan–Meier curves showed a reduced survival time according to c-FLIP_L expression in concert with p53 accumulation (median overall survival (OS): 35 months) compared with lack of expression of both markers (median OS: 110 months; log-rank test, P value=0.024). The multivariable Cox regression model, adjusted for known prognostic factors, identified c-FLIP_L expression, but not p53 nuclear accumulation, as an independent prognostic factor for adverse outcome (hazard ratio=1.82, 95% CI=1.17–2.82; P=0.008). Altogether these data support the independent contribution of c-FLIP_L in refining the prognostic information obtained from standard clinical–pathological indicators, confirming its pivotal role in promoting cell survival.