Abstract
BackgroundTranscription factors forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) have been reported to play important roles in various cancers. However, their role in epithelial ovarian cancer (EOC) has not been elucidated yet. Therefore, we evaluated the expression and clinical significance of FOXO1 and PAX3 in EOC.MethodsImmunohistochemical analyses of FOXO1 and PAX3 in 212 EOCs, 57 borderline ovarian tumors, 153 benign epithelial ovarian tumors, and 79 nonadjacent normal epithelial tissues were performed using tissue microarray. Various clinicopathological variables, including the survival of EOC patients, were compared. In addition, the effect of FOXO1 on cell growth was assessed in EOC cell lines.ResultsFOXO1 and PAX3 protein expression levels were significantly higher in EOC tissues than in nonadjacent normal epithelial tissues, benign tissues, and borderline tumors (all p < 0.001). In EOC tissues, FOXO1 expression was positively correlated with PAX3 expression (Spearman’s rho = 0.118, p = 0.149). Multivariate survival analysis revealed that high FOXO1 expression (hazard ratio = 2.77 [95% CI, 1.48–5.18], p = 0.001) could be an independent prognostic factor for overall survival. Most importantly, high expression of both FOXO1 and PAX3 showed a high hazard ratio (4.60 [95% CI, 2.00–10.55], p < 0.001) for overall survival. Also in vitro results demonstrated that knockdown of FOXO1 was associated with decreased cell viability, migration, and colony formation.ConclusionsThis study revealed that high expression of FOXO1/PAX3 is an indicator of poor prognosis in EOC. Our results suggest the promising potential of FOXO1 and PAX3 as prognostic and therapeutic markers. The possible link between biological functions of FOXO1 and PAX3 in EOC warrants further studies.
Highlights
Transcription factors forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) have been reported to play important roles in various cancers
Most FOXO1 immunoreactivity was observed in the cytoplasm, while most PAX3 immunoreactivity was in the nucleus (Fig. 1a)
IHC scores for FOXO1 and PAX3 are summarized in Table 1, and data revealed that FOXO1 and PAX3 expression levels were significantly higher in epithelial ovarian cancer (EOC) tissues than in borderline tumors, benign tumors, and nonadjacent normal epithelial tissues
Summary
Transcription factors forkhead box protein O1 (FOXO1) and paired box 3 (PAX3) have been reported to play important roles in various cancers. Their role in epithelial ovarian cancer (EOC) has not been elucidated yet. We evaluated the expression and clinical significance of FOXO1 and PAX3 in EOC. Despite significant improvements in the diagnosis and treatment of EOC, more than 70% of women are diagnosed at advanced stages, and the majority of them tend to relapse and die. There is a great need for research to understand the molecular pathogenesis of ovarian cancer and spur the development of more specific and effective prognostic markers to improve patient outcomes. The forkhead box (FOX) family of proteins consists of 19 sub-families of transcription factors. FOXO sub-family consists of four members, FOXO1, FOXO3, FOXO4, and FOXO6, with high protein homology [2] that are involved in diverse intracellular signaling pathways, such as phosphorylation through the phosphoinositide 3-kinas (PI3K)/ protein kinase B (AKT) signaling pathway, and these FOXO members regulate cell-cycle arrest, apoptosis, DNA damage repair, and detoxification of reactive oxygen species by regulating specific genes [3,4,5]
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