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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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Effects of FOXM1 on stemness in the paired ovarian cancer cell lines A2780 and A2780CP70(A) Western blots of stem cell markers and the internal control β-ACTIN. (B) Upper panels: A2780 cells were stably transfected with vector alone or vector encoding FOXM1 (FOXM1 #a and #b). Lower panels: A2780CP70 cells were stably transfected with vector alone or vector encoding shFOXM1 (shFOXM1 #a and #b). Representative phase contrast images of the suspension spheres were taken on a widefield microscope. Scale bars, 100 μm.
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Figure 4: Effects of FOXM1 on stemness in the paired ovarian cancer cell lines A2780 and A2780CP70(A) Western blots of stem cell markers and the internal control β-ACTIN. (B) Upper panels: A2780 cells were stably transfected with vector alone or vector encoding FOXM1 (FOXM1 #a and #b). Lower panels: A2780CP70 cells were stably transfected with vector alone or vector encoding shFOXM1 (shFOXM1 #a and #b). Representative phase contrast images of the suspension spheres were taken on a widefield microscope. Scale bars, 100 μm.

Mentions: We examined sphere formation and the expression of stem cell markers in cisplatin-resistant and paclitaxel-resistant IGROV1 cells. Figure 2A shows that chemoresistant cells formed non-adherent spheres, whereas parental cells did not. Cisplatin-resistant cells formed more spheres than paclitaxel-resistant cells (Fig. 2B), and cells selected with a higher dose of cisplatin (CP2) formed larger spheres (> 50 μm) than cells selected with a lower dose of cisplatin (CP1) (Fig. S1). Chemoresistant cells expressed higher amounts of the stem cell markers BMI1, CD44, NANOG, SOX-2, and MYD88 than parental cells (Fig. 2C). We also examined the expression of stem cell markers in the canonical cisplatin-sensitive and cisplatin-resistant ovarian cancer cell limes A2780 (IC50 = 5.70 μM) and A2780CP70 (IC50 = 30.66 μM) (Fig. 3A). Our results showed that A2780CP70 cells overexpressed several stem cells markers as well as FOXM1 (Fig. 4A).


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)

Effects of FOXM1 on stemness in the paired ovarian cancer cell lines A2780 and A2780CP70(A) Western blots of stem cell markers and the internal control β-ACTIN. (B) Upper panels: A2780 cells were stably transfected with vector alone or vector encoding FOXM1 (FOXM1 #a and #b). Lower panels: A2780CP70 cells were stably transfected with vector alone or vector encoding shFOXM1 (shFOXM1 #a and #b). Representative phase contrast images of the suspension spheres were taken on a widefield microscope. Scale bars, 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Effects of FOXM1 on stemness in the paired ovarian cancer cell lines A2780 and A2780CP70(A) Western blots of stem cell markers and the internal control β-ACTIN. (B) Upper panels: A2780 cells were stably transfected with vector alone or vector encoding FOXM1 (FOXM1 #a and #b). Lower panels: A2780CP70 cells were stably transfected with vector alone or vector encoding shFOXM1 (shFOXM1 #a and #b). Representative phase contrast images of the suspension spheres were taken on a widefield microscope. Scale bars, 100 μm.
Mentions: We examined sphere formation and the expression of stem cell markers in cisplatin-resistant and paclitaxel-resistant IGROV1 cells. Figure 2A shows that chemoresistant cells formed non-adherent spheres, whereas parental cells did not. Cisplatin-resistant cells formed more spheres than paclitaxel-resistant cells (Fig. 2B), and cells selected with a higher dose of cisplatin (CP2) formed larger spheres (> 50 μm) than cells selected with a lower dose of cisplatin (CP1) (Fig. S1). Chemoresistant cells expressed higher amounts of the stem cell markers BMI1, CD44, NANOG, SOX-2, and MYD88 than parental cells (Fig. 2C). We also examined the expression of stem cell markers in the canonical cisplatin-sensitive and cisplatin-resistant ovarian cancer cell limes A2780 (IC50 = 5.70 μM) and A2780CP70 (IC50 = 30.66 μM) (Fig. 3A). Our results showed that A2780CP70 cells overexpressed several stem cells markers as well as FOXM1 (Fig. 4A).

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