Abstract
Ovarian cancer has the highest mortality rate of all gynecological cancers with a high recurrence rate. It is important to understand the nature of recurring cancer cells to terminally eliminate ovarian cancer. The winged helix transcription factor Forkhead box P1 (FOXP1) has been reported to function as either oncogene or tumor-suppressor in various cancers. In the current study, we show that FOXP1 promotes cancer stem cell-like characteristics in ovarian cancer cells. Knockdown of FOXP1 expression in A2780 or SKOV3 ovarian cancer cells decreased spheroid formation, expression of stemness-related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment, whereas overexpression of FOXP1 in A2780 or SKOV3 ovarian cancer cells increased spheroid formation, expression of stemness-related genes and epithelial to mesenchymal transition-related genes, cell migration, and resistance to Paclitaxel or Cisplatin treatment. In addition, overexpression of FOXP1 increased promoter activity of ABCG2, OCT4, NANOG, and SOX2, among which the increases in ABCG2, OCT4, and SOX2 promoter activity were dependent on the presence of FOXP1-binding site. In xenotransplantation of A2780 ovarian cancer cells into nude mice, knockdown of FOXP1 expression significantly decreased tumor size. These results strongly suggest FOXP1 functions as an oncogene by promoting cancer stem cell-like characteristics in ovarian cancer cells. Targeting FOXP1 may provide a novel therapeutic opportunity for developing a relapse-free treatment for ovarian cancer patients.
Highlights
Among all gynecologic cancers, ovarian cancer is a highly fatal disease and a major contributor to cancer-related death in women [1]
To determine whether expression of Forkhead box P1 (FOXP1) is related to development of cancer stem cells (CSCs) in ovarian cancer, the expression levels of FOXP1 during the spheroid culture of A2780 ovarian cancer cells were evaluated
When spheroids were subjected to immunocytochemistry analysis, FOXP1 expression increased along with the transcription factor hypoxia-inducible factor-1α (HIF-1α) inside spheroids (Figure 1D)
Summary
Ovarian cancer is a highly fatal disease and a major contributor to cancer-related death in women [1]. The standard treatment for ovarian cancer is based on the combination of surgery and chemotherapy. The relapse rate is high after cytoreductive surgery and systemic chemotherapy. Understanding the mechanism of metastasis and resistance to chemotherapy in ovarian cancer is very important in order to improve clinical outcomes. Previous studies reported that ovarian cancer contained a small fraction of cells that exhibited enhanced tumor initiating potential and stem cell-like properties, called cancer stem cells (CSCs) [3,4,5]. CSCs derived from ovarian cancer are characterized by their self-renewing capability, high tumorigenicity, and resistance to chemotherapy and radiotherapy [6]. CSCs have been suggested as the cause of tumor metastasis and tumor relapse because patients with residual ovarian CSCs acquire chemoresistance after standard combination of surgery and chemotherapy [7, 8]
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