Abstract
Epithelial ovarian cancer (EOC) is a highly lethal disease with poor prognosis especially in advanced stage tumor. Emerging evidence has reported that aberrant upregulation of FoxM1 and β-catenin are closely associated with aggressiveness of human cancer. However, interplay between these factors in the aggressiveness of EOC is not fully illustrated. In this study, we show that FoxM1 is frequently increased in Middle Eastern EOC and associated with high proliferative index (p = 0.0007) and high grade tumor (p = 0.0024). Interestingly, FoxM1 is significantly associated with elevated nuclear β-catenin and the concomitant increase of FoxM1 and β-catenin is associated with advanced stage of EOC by immunohistochemical analysis of 261 samples of Saudi patients with EOC. Functional analysis showed that β-catenin is a direct transcriptional target of FoxM1 in EOC cell lines. FoxM1 inhibition either by specific inhibitor, thiostrepton or siRNA suppressed β-catenin expression, whereas overexpression of FoxM1 increased nuclear β-catenin expression. We identified two FoxM1 binding sites in the β-catenin promoter that specifically bound to FoxM1 protein. Down-regulation of FoxM1 using thiostrepton induced apoptosis and inhibited cell migration/invasion in EOC cells. Moreover, co-inhibition of FoxM1 by thiostrepton and β-catenin by FH535 significantly and synergistically inhibited EOC cell growth in vitro and in vivo. Collectively, our findings confer that co-targeting FoxM1/β-catenin signaling cascade may be a promising molecular therapeutic choice in advanced EOC.
Highlights
Ovarian cancer is the most lethal and the second most commonly diagnosed disease among all gynecological malignancies worldwide [1,2,3]
Forkhead box M1 (FoxM1) is significantly associated with high proliferation and high grade Epithelial ovarian cancer (EOC)
In order to gain insight into biological plausibility of FoxM1/βcatenin overexpression in the pathogenesis of EOC, which would be suggested by our findings above, we first set out to test the potential role of FoxM1 in relevant EOC cell lines
Summary
Ovarian cancer is the most lethal and the second most commonly diagnosed disease among all gynecological malignancies worldwide [1,2,3]. The high mortality rate of ovarian cancer is due to its poor prognosis and majority of the cases are diagnosed with advanced stage disease [4]. Ovarian cancer is a heterogeneous tumor with a wide range of clinical presentations, cytological features and genetic alterations [5, 6]. Ovarian high-grade cancers are characterized by highgrade nuclei, poor differentiation, a high mitotic index, less responsive to chemotherapy, more aggressiveness as well as low survival rate [6,7,8]. The relatively worse pathogenesis and clinicopathologic features of high-grade ovarian cancers cause poor clinical management of this type of disease. Understanding the underlying molecular mechanisms may assist in developing better curative therapy in aggressive ovarian cancers
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