Overexpression of FOXG1 contributes to TGF-β resistance through inhibition of p21WAF1/CIP1 expression in ovarian cancer

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Background:Loss of growth inhibitory response to transforming growth factor-β (TGF-β) is a common feature of epithelial cancers. Recent studies have reported that genetic lesions and overexpression of oncoproteins in TGF-β/Smads signalling cascade contribute to the TGF-β resistance. Here, we showed that the overexpressed FOXG1 was involved in attenuating the anti-proliferative control of TGF-β/Smads signalling in ovarian cancer.Methods:FOXG1 and p21WAF1/CIP1 expressions were evaluated by real-time quantitative reverse-transcription polymerase chain reaction (RT–PCR), western blot and immunohistochemical analyses. The effect of FOXG1 on p21WAF1/CIP1 transcriptional activity was examined by luciferase reporter assays. Cell lines stably expressing or short hairpin RNA interference-mediated knockdown FOXG1 were established for studying the gain-or-loss functional effects of FOXG1. XTT cell proliferation assay was used to measure cell growth of ovarian cancer cells.Results:Quantitative RT–PCR and western blot analyses showed that FOXG1 was upregulated and inversely associated with the expression levels of p21WAF1/CIP1 in ovarian cancer. The overexpression of FOXG1 was significantly correlated with high-grade ovarian cancer (P=0.025). Immunohistochemical analysis on ovarian cancer tissue array was further evidenced that FOXG1 was highly expressed and significantly correlated with high-grade ovarian cancer (P=0.048). Functionally, enforced expression of FOXG1 selectively blocked the TGF-β-induced p21WAF1/CIP1 expressions and increased cell proliferation in ovarian cancer cells. Conversely, FOXG1 knockdown resulted in a 20–26% decrease in cell proliferation together with 16–33% increase in p21WAF1/CIP1 expression. Notably, FOXG1 was able to inhibit the p21WAF1/CIP1 promoter activity in a p53-independent manner by transient reporter assays.ConclusionOur results suggest that FOXG1 acts as an oncoprotein inhibiting TGF-β-mediated anti-proliferative responses in ovarian cancer cells through suppressing p21WAF1/CIP1 transcription.