Forkhead box transcription factor FoxG1 is over-expressed in ovarian cancer and can inhibit p21 expression

Abstract

Loss of transforming growth factor-β (TGF-β) mediated anti-proliferative responses is one of the major causes of tumor growth. However, several reports have suggested that TGF-β signaling components remain intact in ovarian cancer, and therefore leaving the mechanism of TGF-β resistance involved in ovarian cancer remains unknown. Previous studies have demonstrated that FoxG1 abolishes the TGF-β mediated growth inhibition by suppressing the transcription activation of p21in several human cancers. Besides, an inverse relationship between FoxG1 and p21 expression has been observed. In our own study, in 8 ovarian cancer cell lines studied, 5 of them showed Smad3 activation and p21 induction upon TGF-β treatment, suggesting that these 5 cell lines acquire functional TGF-β signaling components. Our cDNA microarray data shows that the expression level of FoxG1 in ovarian cancer cell lines is 2.2 fold higher than that in human ovarian surface epithelial cells. Quantitative RT-PCR confirmed the up-regulation of FoxG1 mRNA expression in ovarian tumor tissues. Furthermore, immunohistochemical analysis demonstrated that 70% of ovarian carcinomas over-expressed FoxG1. Therefore, we hypothesize that FoxG1 may have a significant oncogenic role in ovarian cancer. Enforced expression of FoxG1 in two ovarian cancer cell lines, A2780cp and SKOV3, selectively blocked the TGF-β-induced p21 activation and showed an increase in cell proliferation. In addition, knockdown of FoxG1 expression in SKOV3 cell line using FoxG1 specific shRNA resulted in a decrease in cell proliferation together with 2 fold increase in p21 expression. Transient reporter assay on HEK293 and A2780cp cell lines also showed that FoxG1 inhibited the p21 promoter activity at transcriptional level. These data suggest the participation of FoxG1 in the loss of the TGF-β mediated anti-proliferative responses in ovarian cancer cells by suppressing the transcription level of p21. We are currently using other in vitro and in vivo experiments to further characterize the functions of FoxG1. Our findings represent the first report of the potential oncogenic role of FoxG1 in ovarian cancer.