Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Oncol Rep. 2019 Oct;42(4):1307-1318. doi: 10.3892/or.2019.7248. Epub 2019 Jul 25.
Hypoxia is a tumorigenesis‑related microenvironment change which usually occurs in the earliest stage of prostate cancer (PCa) development. Accumulating evidence has demonstrated that hypoxia/hypoxia‑inducing factor (HIF) is involved in the induction of epithelial‑mesenchymal transition (EMT) and increased metastatic potential in PCa. However, the mechanism by which hypoxia/HIF regulates EMT remains unclear. In the present study, we demonstrated the molecular mechanisms of hypoxia‑induced EMT in PCa, focusing on HIF‑1α/Forkhead box M1 (FoxM1) signaling pathway. PCa PC3 and DU145 cell lines were used as the model system in vitro. Our data revealed that hypoxia induced EMT in PCa cells. Bioinformatics analysis identified the possible association between HIF‑1α and FoxM1. Additionally, FoxM1 was significantly associated with PCa development and Gleason scores of PCa. Exposure to hypoxia resulted in the increased expression of HIF‑1α and FoxM1. Genetic knockdown FoxM1 abolished hypoxia‑induced EMT in PCa, while exogenous overexpression of FoxM1 facilitated hypoxia‑induced EMT. Furthermore, the increase of FoxM1 during hypoxia was due to the transcriptional regulation on the FoxM1 promoter by HIF‑1α. We also confirmed the binding site of HIF‑1α on the FoxM1 promoter by different lengths promoter sequences. These findings provide new insights into how EMT is regulated in PCa under hypoxic stress. It is worthwhile to investigate in future that inhibition of FoxM1 as a potential target may be an effective therapeutic strategy against PCa.
缺氧是肿瘤发生相关的微环境改变，通常发生在前列腺癌（PCa）发展的最早阶段。越来越多的证据表明，缺氧/缺氧诱导因子（HIF）参与诱导上皮-间充质转化（EMT）和增加 PCa 的转移潜力。然而，缺氧/HIF 调节 EMT 的机制尚不清楚。在本研究中，我们研究了缺氧诱导 PCa 中 EMT 的分子机制，重点关注 HIF-1α/叉头框 M1（FoxM1）信号通路。体外使用 PCa PC3 和 DU145 细胞系作为模型系统。我们的数据表明，缺氧诱导 PCa 细胞发生 EMT。生物信息学分析鉴定了 HIF-1α 和 FoxM1 之间的可能关联。此外，FoxM1 与 PCa 的发生和 Gleason 评分显著相关。暴露于缺氧会导致 HIF-1α 和 FoxM1 的表达增加。遗传敲低 FoxM1 可消除缺氧诱导的 PCa 中 EMT，而过表达 FoxM1 则促进缺氧诱导的 EMT。此外，FoxM1 在缺氧期间的增加是由于 HIF-1α 对 FoxM1 启动子的转录调节。我们还通过不同长度的启动子序列证实了 HIF-1α 在 FoxM1 启动子上的结合位点。这些发现为缺氧应激下 PCa 中 EMT 如何受到调节提供了新的见解。值得在未来研究中探讨抑制 FoxM1 作为潜在靶点是否可能成为治疗 PCa 的有效策略。
