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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-08-0218v1 16/2/443    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Bagnoli, M. Articles by Mezzanzanica, D. Search for Related Content PubMed PubMed Citation Articles by Bagnoli, M. Articles by Mezzanzanica, D.

M Bagnoli, Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
F Ambrogi, Institute of Medical Statistics and Biometry, Universita degli Studi di Milano, Milan, Italy
S Pilotti, Anatomy Patology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
P Alberti, Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
A Ditto, Surgical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
M Barbareschi, Pathology, S. Chiara Hospital, Trento, Italy
E Galligioni, Gynecological Surgery, S. Chiara Hospital, Trento, Italy
E Biganzoli, Unit of Medical Statistics and Biometry, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
S Canevari, Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
D Mezzanzanica, Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

Correspondence: Silvana Canevari, Email: silvana.canevari{at}istitutotumori.mi.it

Abstract

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, the long isoform of cellular FLICE inhibitory protein (c-FLIP) accounts for apoptosis resistance in a context of functional p53 and resistance could be overcome by c-FLIP downmodulation. Here we studied the association between c-FLIP and p53 expression and their prognostic impact in EOC patients. Tumor tissue from 207 patients diagnosed with primary EOC was analyzed by immunohistochemistry for c-FLIP and p53 expression and multiple correspondence analysis (MCA) was used to evaluate the multivariable pattern of association among patients' clinical-pathological characteristics and biological determinants. Immunohistochemistry revealed c-FLIP expression and p53 nuclear accumulation inversely related (P=0.0001; OR=0.29, CI=0.15-.055). MCA indicated that p53 accumulation was associated to clinical-pathological variables, while c-FLIP expression contributed to the overall association pattern independently from others clinical characteristics and complementary to p53. Kaplan-Meier curves showed a reduced survival time according to c-FLIP expression in concert with p53 accumulation (median OS: 35 months) compared to 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 expression, but not p53 nuclear accumulation, as an independent prognostic factor for adverse outcome (HR=1.82, 95%CI=1.17-2.82, p-value=0.008). Altogether these data support the independent contribution of c-FLIP in refining the prognostic information obtained from standard clinical-pathological indicators, confirming its pivotal role in promoting cell survival.