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FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells.

Chiu WT, Huang YF, Tsai HY, Chen CC, Chang CH, Huang SC, Hsu KF, Chou CY - Oncotarget (2015)

Bottom Line: Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer.Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells.The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.

ABSTRACT
Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1-expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of β-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer.

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Effect of the WNT/β-CATENIN signaling on FOXM1 expression(A) Western blots of FOXM1 and the internal control β-ACTIN in whole cell lysates of A2780CP70 cells treated for 2 days with different concentrations of WNT3A and SFRP5 peptides. (B) Ad293 cells were transfected with the indicated concentrations of pcDNA3.1 (control vector) or pcDNA3.1 encoding SFRP5 and 500 ng pLuc-FOXM1 (FOXM1 promoter luciferase vector). The cells were harvested two days after transfection, and dual luciferase reporter assays were performed. FOXM1 promoter activity was expressed as the fold change relative to the control (pcDNA3.1). Each bars represents mean ± standard error of the mean from three independent experiments. **: P < 0.01; ***: P < 0.001. (C and D) Western blots of SFRP5, FOXM1, and the internal control β-ACTIN in Ad293 cells overexpressing a control vector (Vector) or shSFRP5 vector (shSFRP5) (C), and ES-2 and TOV-21G cells (D).
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Figure 9: Effect of the WNT/β-CATENIN signaling on FOXM1 expression(A) Western blots of FOXM1 and the internal control β-ACTIN in whole cell lysates of A2780CP70 cells treated for 2 days with different concentrations of WNT3A and SFRP5 peptides. (B) Ad293 cells were transfected with the indicated concentrations of pcDNA3.1 (control vector) or pcDNA3.1 encoding SFRP5 and 500 ng pLuc-FOXM1 (FOXM1 promoter luciferase vector). The cells were harvested two days after transfection, and dual luciferase reporter assays were performed. FOXM1 promoter activity was expressed as the fold change relative to the control (pcDNA3.1). Each bars represents mean ± standard error of the mean from three independent experiments. **: P < 0.01; ***: P < 0.001. (C and D) Western blots of SFRP5, FOXM1, and the internal control β-ACTIN in Ad293 cells overexpressing a control vector (Vector) or shSFRP5 vector (shSFRP5) (C), and ES-2 and TOV-21G cells (D).

Mentions: The frizzled-related proteins (SFRPs) are secreted signaling molecules that antagonize WNT/β-CATENIN signaling. We examined the effects of SFRP5 and an activator of WNT/β-CATENIN signaling (WNT3A) on FOXM1 expression in A2780CP70 cells. When added to the culture medium, WNT3A increased FOXM1 expression, and SFRP5 decreased FOXM1 expression, in a dose-dependent manner (Fig. 9A). Overexpression of SFRP5 inhibited the activity of the FOXM1 promoter in a dose-dependent manner, whereas SFRP5 silencing increased FOXM1 expression (Fig. 9B, C). In addition, SFRP5 expression inversely correlated with FOXM1 expression in ES-2 and TOV-21G ovarian cancer cells (Fig. 9D).


FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells.

Chiu WT, Huang YF, Tsai HY, Chen CC, Chang CH, Huang SC, Hsu KF, Chou CY - Oncotarget (2015)

Effect of the WNT/β-CATENIN signaling on FOXM1 expression(A) Western blots of FOXM1 and the internal control β-ACTIN in whole cell lysates of A2780CP70 cells treated for 2 days with different concentrations of WNT3A and SFRP5 peptides. (B) Ad293 cells were transfected with the indicated concentrations of pcDNA3.1 (control vector) or pcDNA3.1 encoding SFRP5 and 500 ng pLuc-FOXM1 (FOXM1 promoter luciferase vector). The cells were harvested two days after transfection, and dual luciferase reporter assays were performed. FOXM1 promoter activity was expressed as the fold change relative to the control (pcDNA3.1). Each bars represents mean ± standard error of the mean from three independent experiments. **: P < 0.01; ***: P < 0.001. (C and D) Western blots of SFRP5, FOXM1, and the internal control β-ACTIN in Ad293 cells overexpressing a control vector (Vector) or shSFRP5 vector (shSFRP5) (C), and ES-2 and TOV-21G cells (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4385856&req=5

Figure 9: Effect of the WNT/β-CATENIN signaling on FOXM1 expression(A) Western blots of FOXM1 and the internal control β-ACTIN in whole cell lysates of A2780CP70 cells treated for 2 days with different concentrations of WNT3A and SFRP5 peptides. (B) Ad293 cells were transfected with the indicated concentrations of pcDNA3.1 (control vector) or pcDNA3.1 encoding SFRP5 and 500 ng pLuc-FOXM1 (FOXM1 promoter luciferase vector). The cells were harvested two days after transfection, and dual luciferase reporter assays were performed. FOXM1 promoter activity was expressed as the fold change relative to the control (pcDNA3.1). Each bars represents mean ± standard error of the mean from three independent experiments. **: P < 0.01; ***: P < 0.001. (C and D) Western blots of SFRP5, FOXM1, and the internal control β-ACTIN in Ad293 cells overexpressing a control vector (Vector) or shSFRP5 vector (shSFRP5) (C), and ES-2 and TOV-21G cells (D).
Mentions: The frizzled-related proteins (SFRPs) are secreted signaling molecules that antagonize WNT/β-CATENIN signaling. We examined the effects of SFRP5 and an activator of WNT/β-CATENIN signaling (WNT3A) on FOXM1 expression in A2780CP70 cells. When added to the culture medium, WNT3A increased FOXM1 expression, and SFRP5 decreased FOXM1 expression, in a dose-dependent manner (Fig. 9A). Overexpression of SFRP5 inhibited the activity of the FOXM1 promoter in a dose-dependent manner, whereas SFRP5 silencing increased FOXM1 expression (Fig. 9B, C). In addition, SFRP5 expression inversely correlated with FOXM1 expression in ES-2 and TOV-21G ovarian cancer cells (Fig. 9D).

Bottom Line: Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer.Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells.The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.

ABSTRACT
Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1-expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of β-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer.

Show MeSH
Related in: MedlinePlus