Forkhead Box Protein C2 (FOXC2) Promotes the Resistance of Human Ovarian Cancer Cells to Cisplatin In Vitro and In Vivo.

BACKGROUND/AIMS FOXC2 has been reported to play a role in tumor progression, but the correlations of FOXC2 with the cisplatin (CDDP) resistance of ovarian cancer cells are still unclear. The purpose of the present study is to investigate the roles of FOXC2 in the CDDP resistance of ovarian cancer cells and its possible mechanisms. METHODS Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of FOXC2 mRNA in CDDP-resistant or sensitive ovarian cancer tissues and cell lines (SKOV3/CDDP and SKOV3). Gain- and loss-of-function assays were performed to analyze the effects of FOXC2 knockdown or overexpression on the in vitro and in vivo sensitivity of ovarian cancer cells to CDDP and its possible molecular mechanisms. RESULTS The relative expression level of FOXC2 mRNA in CDDP-resistant ovarian cancer tissues was higher than that in CDDP-sensitive tissues. Also, the expression of FOXC2 mRNA and protein in CDDP-resistant ovarian cancer cell line (SKOV3/CDDP) cell line was higher than that in its parental cell line (SOKV3). Small hairpin RNA (shRNA)-mediated FOXC2 knockdown significantly increased the in vitro and in vive sensitivity of SKOV3/CDDP cells to CDDP by enhancing apoptosis, while upregulation of FOXC2 significantly decreased the in vitro and in vivo sensitivity of SKOV3 cells to CDDP by reducing apoptosis. Furthermore, FOXC2 activates the Akt and MAPK signaling pathways, and then induced the decreased expression of Bcl-2 protein and the increased expression of Bax and cleaved caspase-3 proteins. CONCLUSIONS FOXC2 mediates the CDDP resistance of ovarian cancer cells by activation of the Akt and MAPK signaling pathways, and may be a potential novel therapeutic target for overcoming CDDP resistance in human ovarian cancer.