c-FLIPL expression defines two ovarian cancer patient subsets and is a prognostic factor of adverse outcome

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, 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.