Aberrant expression of WWOX protein in epithelial ovarian cancer: a clinicopathologic and immunohistochemical study.
ABSTRACT Epithelial ovarian cancer is the most frequent cause of death from gynecologic cancer. The WW domain-containing oxidoreductase (WWOX) gene is located at 16q23.3-24.1, a region that spans the second most common human fragile site, FRA16D. Abnormalities affecting WWOX at the genomic and/or expression level(s) have been reported in numerous neoplasias and cancer-derived cell lines. The goal of the study was to evaluate WWOX protein expression in epithelial ovarian carcinoma tissues to determine whether they correlated with clincopathologic parameters. We performed WWOX expression analyses by means of immunohistochemistry on 112 epithelial ovarian carcinoma tissues, and ovarian carcinoma-derived SKOV3, 3AO cells. The basic significant level was fixed at P<0.05. Loss of WWOX expression was observed in 32 (28.6%) of 112 ovarian carcinoma samples and was positively correlated with negative estrogen receptor (ER) (P<0.001) and negative progesterone receptor (PR) (P=0.001). A statistically significant correlation was observed between the lack of WWOX expression and the advanced International Federation of Gynecology and Obstetrics (FIGO) stages (P=0.02). Furthermore, negative WWOX staining was significantly correlated with lymph node metastasis (P=0.013), whereas no significant differences were found between WWOX and HER-2/neu staining (P=0.79). WWOX protein expression was moderately detectable in SKOV3 cells but not in 3AO cells. Our results indicate that loss of WWOX expression in epithelial ovarian carcinomas correlates with negative ER, negative PR, advanced FIGO stages, and lymph node metastases.
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ABSTRACT: Casticin, a polymethoxyflavone, is reported to have anticancer activities. The aim of the present study was to examine the molecular mechanisms by which casticin induces apoptosis in ovarian cancer cells. The human ovarian cancer cell lines SKOV3 and A2780 were cultured in vitro. Various molecular techniques, including histone/DNA enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction (RT-PCR), western blot analysis and gene transfection, were used to assess the expression of FOXO3a and forkhead box protein M1 (FoxM1) in casticin-treated ovarian cancer cell lines. Casticin-induced apoptotic cell death was accompanied by the activation of transcription factor FOXO3a, with a concomitant decrease in the expression levels of FoxM1 and its downstream target factors, namely survivin and polo-like kinase 1 (PLK1), and an increase in p27(KIP1). A small inhibitory RNA (siRNA) knockout of FoxM1 potentiated casticin-induced apoptosis in ovarian cancer cells. Silencing FOXO3a expression using siRNA increased FoxM1 expression levels and clearly attenuated the induction of apoptosis by casticin treatment. These results show that casticin-induced apoptosis in ovarian cancer may be caused by the activation of FOXO3a, leading to FoxM1 inhibition.Oncology letters 05/2013; 5(5):1605-1610. · 0.24 Impact Factor