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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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FOXM1 is essential for nuclear localization of β-CATENINCP1, CP2, and TX0.005 cells received control siRNA (siControl) or FOXM1 siRNA (siFOXM1) for 48 hours. Immunofluorescence staining of the nucleus, β-CATENIN, and FOXM1 in the three cell lines is shown. Representative fluorescence images were taken on a confocal microscope under excitation at 405 nm, 488 nm or 543 nm. Scale bars, 20 μm.
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Figure 8: FOXM1 is essential for nuclear localization of β-CATENINCP1, CP2, and TX0.005 cells received control siRNA (siControl) or FOXM1 siRNA (siFOXM1) for 48 hours. Immunofluorescence staining of the nucleus, β-CATENIN, and FOXM1 in the three cell lines is shown. Representative fluorescence images were taken on a confocal microscope under excitation at 405 nm, 488 nm or 543 nm. Scale bars, 20 μm.

Mentions: Total β-CATENIN expression and activation (indicated by β-CATENIN dephosphorylation) were higher in both cisplatin-resistant and paclitaxel-resistant IGROV1 cells than parental cells, as was expression of c-MYC, which is encoded by a β-CATENIN target gene (Fig. 7A) Chemoresistant cells had higher nuclear levels of FOXM1 and β-CATENIN than parental cells. Immunofluorescence staining revealed that β-CATENIN was located in the plasma membrane between cell-cell junctions (where it mediates adherence) in parental cells. In chemoresistant cells, it was mostly cytoplasmic or nuclear (Fig. 7B), and nuclear β-CATENIN co-localized with FOXM1 (Fig. 7C). Knockdown of FOXM1 impaired nuclear localization and accumulation of β-CATENIN in both cisplatin-resistant and paclitaxel-resistant IGROV1 cells (Fig. 8).


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)

FOXM1 is essential for nuclear localization of β-CATENINCP1, CP2, and TX0.005 cells received control siRNA (siControl) or FOXM1 siRNA (siFOXM1) for 48 hours. Immunofluorescence staining of the nucleus, β-CATENIN, and FOXM1 in the three cell lines is shown. Representative fluorescence images were taken on a confocal microscope under excitation at 405 nm, 488 nm or 543 nm. Scale bars, 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: FOXM1 is essential for nuclear localization of β-CATENINCP1, CP2, and TX0.005 cells received control siRNA (siControl) or FOXM1 siRNA (siFOXM1) for 48 hours. Immunofluorescence staining of the nucleus, β-CATENIN, and FOXM1 in the three cell lines is shown. Representative fluorescence images were taken on a confocal microscope under excitation at 405 nm, 488 nm or 543 nm. Scale bars, 20 μm.
Mentions: Total β-CATENIN expression and activation (indicated by β-CATENIN dephosphorylation) were higher in both cisplatin-resistant and paclitaxel-resistant IGROV1 cells than parental cells, as was expression of c-MYC, which is encoded by a β-CATENIN target gene (Fig. 7A) Chemoresistant cells had higher nuclear levels of FOXM1 and β-CATENIN than parental cells. Immunofluorescence staining revealed that β-CATENIN was located in the plasma membrane between cell-cell junctions (where it mediates adherence) in parental cells. In chemoresistant cells, it was mostly cytoplasmic or nuclear (Fig. 7B), and nuclear β-CATENIN co-localized with FOXM1 (Fig. 7C). Knockdown of FOXM1 impaired nuclear localization and accumulation of β-CATENIN in both cisplatin-resistant and paclitaxel-resistant IGROV1 cells (Fig. 8).

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