Reactive oxygen species regulate FSH-induced expression of vascular endothelial growth factor via Nrf2 and HIF1α signaling in human epithelial ovarian cancer

Zhang,Zhenbo; Wang,Qianqian; Ma,Jie; Yi,Xiaofang; Zhu,Yaping; Xi,Xiaowei; Feng,Youji; Jin,Zhijun

doi:10.3892/or.2013.2278

Reactive oxygen species regulate FSH-induced expression of vascular endothelial growth factor via Nrf2 and HIF1α signaling in human epithelial ovarian cancer

Authors:
- Zhenbo Zhang
- Qianqian Wang
- Jie Ma
- Xiaofang Yi
- Yaping Zhu
- Xiaowei Xi
- Youji Feng
- Zhijun Jin
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Affiliations: Department of Obstetrics and Gynecology, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai, P.R. China, Department of Obstetrics and Gynecology, Changzheng Hospital, The Second Military Medical University, Shanghai, P.R. China, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P.R. China
Published online on: February 6, 2013 https://doi.org/10.3892/or.2013.2278
Pages: 1429-1434

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Abstract

Follicle-stimulating hormone (FSH) and the FSH receptor contribute to tumor angiogenesis and are acknowledged risk factors for ovarian epithelial cancer (OEC). Accumulating evidence suggests that FSH can induce vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1α (HIF1α) expression. We previously demonstrated that FSH induces reactive oxygen species (ROS) production and activates Nrf2 signaling. This study was performed to investigate whether FSH induces VEGF expression via a ROS-mediated Nrf2 signaling pathway. In the current study, OET cells were treated with FSH; dichlorofluorescein staining was used to determine ROS generation, western blotting was used to quantify Nrf2 expression and VEGF expression was measured using an ELISA. Nrf2 and HIF1α were knocked down using siRNAs to investigate the role of the Nrf2 and HIF1α signaling pathways in FSH-induced VEGF expression. The chromatin immunoprecipitation assay (ChIP) was used to determine HIF1α binding to the VEGF promoter. Finally, it was found that FSH induced ROS production and activated Nrf2 signaling; elimination of ROS or knockdown of Nrf2 blocked FSH-induced VEGF expression. Knockdown of Nrf2 impaired HIF1α signaling activation. Blockage of the FSH-ROS-Nrf2-HIF1α signaling pathway attenuated FSH-induced binding of HIF1α to the VEGF promoter. Collectively, this study indicates that ROS and aberrant expression of Nrf2 play an important role in FSH-induced angiogenesis in OEC, and provides insight into the mechanisms of FSH-induced VEGF expression. Elimination of ROS or inhibition of Nrf2 may represent potential therapeutic targets for the treatment of ovarian cancer.

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