Li Chanjuan, Ding Hongjuan, Tian Jing, Wu Lili, Wang Yun, Xing Yuan, Chen Min
Department of Obstetrics and Gynecology, Nanjing Maternity and Child Health Care Hospital to Nanjing Medical University, Nanjing, P.R. China.
Cell Physiol Biochem. 2016;39(1):242-52. doi: 10.1159/000445620. Epub 2016 Jun 24.
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.
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.
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.
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.
背景/目的：已有报道称FOXC2在肿瘤进展中发挥作用，但FOXC2与卵巢癌细胞顺铂（CDDP）耐药性之间的相关性仍不清楚。本研究旨在探讨FOXC2在卵巢癌细胞CDDP耐药中的作用及其可能机制。
采用定量实时PCR（qRT-PCR）检测CDDP耐药或敏感的卵巢癌组织及细胞系（SKOV3/CDDP和SKOV3）中FOXC2 mRNA的表达。进行功能获得和功能缺失实验，分析FOXC2敲低或过表达对卵巢癌细胞体外和体内对CDDP敏感性的影响及其可能的分子机制。
CDDP耐药的卵巢癌组织中FOXC2 mRNA的相对表达水平高于CDDP敏感组织。此外，CDDP耐药的卵巢癌细胞系（SKOV3/CDDP）中FOXC2 mRNA和蛋白的表达高于其亲本细胞系（SOKV3）。小发夹RNA（shRNA）介导的FOXC2敲低通过增强凋亡显著增加了SKOV3/CDDP细胞对CDDP的体外和体内敏感性，而FOXC2的上调通过减少凋亡显著降低了SKOV3细胞对CDDP的体外和体内敏感性。此外，FOXC2激活Akt和MAPK信号通路，进而诱导Bcl-2蛋白表达降低以及Bax和裂解的caspase-3蛋白表达增加。
FOXC2通过激活Akt和MAPK信号通路介导卵巢癌细胞的CDDP耐药，可能是克服人类卵巢癌CDDP耐药的潜在新治疗靶点。
