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: The aim of the present study was to determine the roles of the WWOX tumor suppressor and cancer-related genes in bladder tumor carcinogenesis. Reverse transcription-quantitative polymerase chain reaction was used to analyze the status of WWOX promoter methylation (using MethylScreen™ technology) and loss of heterozygosity (LOH) in papillary urothelial cancer tissues. The associations between the expression levels of the following tumorigenesis-related genes were also assessed: The WWOX tumor suppressor gene, the MKI67 proliferation gene, the BAX, BCL2 and BIRC5 apoptotic genes, the EGFR signal transduction gene, the VEGF vascular endothelial growth factor gene, and the CCND1 and CCNE1 cell cycle genes. The results reveal a high frequency of LOH in intron 1 in the WWOX gene, as well as an association between reduced WWOX expression levels and increased promoter methylation. In addition, the present study demonstrates that in bladder tumors, apoptosis is inhibited by increased expression levels of the BCL2 gene. A correlation between the proliferation indices of the MKI67 and the BIRC5 genes was also revealed. Furthermore, the expression levels of VEGF were identified to be positively associated with those of the EGFR gene.Oncology letters 11/2014; 8(5):2291-2297. · 0.24 Impact Factor
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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
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ABSTRACT: WW-domain-containing oxidoreductase (WWOX) is the tumour suppressor gene from the common fragile site FRA16D, whose altered expression has been observed in tumours of various origins. Its suppressive role and influence on basic cellular processes such as proliferation and apoptosis have been confirmed in many in vitro and in vivo studies. Moreover, its protein is thought to take part in the regulation of tissue morphogenesis and cell differentiation. However, its role in colon cancer formation remains unclear. The aim of this study was to characterize the influence of WWOX on the process of colon cancerogenesis, the basic features of the cancer cell and its expression profiles. Multiple biological tests, microarray experiments and quantitative reverse transcriptase (RT)-PCR were performed on two colon cancer cell lines, HT29 and SW480, which differ in morphology, expression of differentiation markers, migratory characteristics and metastasis potential and which represent negative (HT29) and low (SW480) WWOX expression levels. The cell lines were subjected to retroviral transfection, inducting WWOX overexpression. WWOX was found to have diverse effects on proliferation, apoptosis and the adhesion potential of modified cell lines. Our observations suggest that in the HT29 colon cancer cell line, increased expression of WWOX may result in the transition of cancer cells into a more normal colon epithelium phenotype, while in SW480, WWOX demonstrated well-known tumour suppressor properties. Our results also suggest that WWOX does not behave as classical tumour suppressor gene, and its influence on cell functioning is more global and complicated.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 06/2014;