Department of Obstetrics and Gynecology, Shanghai Jiao Tong University, Affiliated First People's Hospital, Shanghai, PR China.
Oncol Rep. 2013 Apr;29(4):1429-34. doi: 10.3892/or.2013.2278. Epub 2013 Feb 6.
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.
卵泡刺激素（FSH）及其受体促进肿瘤血管生成，是卵巢上皮性癌（OEC）的公认危险因素。越来越多的证据表明，FSH 可以诱导血管内皮生长因子（VEGF）和缺氧诱导因子 1α（HIF1α）的表达。我们之前的研究表明，FSH 诱导活性氧（ROS）的产生并激活 Nrf2 信号通路。本研究旨在探讨 FSH 是否通过 ROS 介导的 Nrf2 信号通路诱导 VEGF 表达。在本研究中，用 FSH 处理 OET 细胞；用二氯荧光素染色测定 ROS 的产生，用 Western blot 定量测定 Nrf2 表达，用 ELISA 测定 VEGF 的表达。用 siRNA 敲低 Nrf2 和 HIF1α，以研究 Nrf2 和 HIF1α 信号通路在 FSH 诱导的 VEGF 表达中的作用。用染色质免疫沉淀试验（ChIP）确定 HIF1α 与 VEGF 启动子的结合。结果发现，FSH 诱导 ROS 的产生并激活 Nrf2 信号通路；消除 ROS 或敲低 Nrf2 阻断了 FSH 诱导的 VEGF 表达。敲低 Nrf2 损害了 HIF1α 信号通路的激活。阻断 FSH-ROS-Nrf2-HIF1α 信号通路减弱了 FSH 诱导的 HIF1α 与 VEGF 启动子的结合。综上所述，本研究表明，ROS 和 Nrf2 的异常表达在 OEC 的 FSH 诱导血管生成中发挥重要作用，并深入了解 FSH 诱导 VEGF 表达的机制。消除 ROS 或抑制 Nrf2 可能成为治疗卵巢癌的潜在治疗靶点。
