Dysregulated expression of stem cell transcription factor Nanog in development and progress of ovarian cancers

Abstract

Introduction: Ovarian cancer is the most lethal of all gynecological malignacies due to its lack of symptoms at early stages. In addition, widespread intraperitoneal metastases and malignant ascites frequently develop. Therefore, it is very important to identify novel prognostic and therapeutic targets for this cancer. Many researchers believe that only a small subset of cancer cells are endowed with stem cell properties, which are responsible for tumor growth, metastatic progression and recurrence. Nanog is one of core transcription factors essential for the maintaining self-renewal and pluripotency in stem cells. This study investigated the clinical significance, functional roles and putative downstream targets of Nanog in ovarian cancer. Methods and Results: Differential protein expression profile of Nanog in clinical samples, including benign (n=6), borderline (n=7), carcinomas (n=97) and metastatic foci (n=24) were determined by immunohistochemistry. Differential mRNA expression pattern of Nanog in 3 normal ovarian epithelial cell lines, 16 ovarian cancer cell lines was assessed by quantitative real-time polymerase chain reaction. Subcellular localization of Nanog was performed by Western blotting. Nanog was found to be localized in the nucleus of ovarian cancers. High Nanog expression in ovarian cancers was significantly associated with high grade tumors, serous histological type and chemoresistance (p<0.05). Importantly, Nanog was found to be highly expressed in ovarian cancer cell lines with metastasis-associated property and in clinical samples of metastatic foci. Elevated Nanog expression was associated with poor overall and disease-free survival in the univariate analysis. Nanog expression became one of the independent prognostic factors in the multivariate analysis for overall but not disease-free survival. By Transwell migration and invasion assays, stable knockdown of Nanog in ovarian cancer cell line, OVCAR-3, impeded cell migration and invasion. Stable knockdown of Nanog also increased mRNA expression of E-cadherin (an essential epithelial mesenchymal transition marker, thus related to metastasis) and FOXO1A (an important gene related to chemoresistance). Conclusion: Nanog was associated with progression of ovarian tumors, patients’ overall survival and chemoresistance, suggesting that Nanog can be one of the potential prognostic markers and therapeutic molecular targets in ovarian cancer.