Yang Jimin, Kim Woo Jean, Jun Hyoung Oh, Lee Eun Ju, Lee Kyeong Won, Jeong Jae-Yeon, Lee Sae-Won
Biomedical Research Institute and IRICT, Seoul National University Hospital, Seoul, Republic of Korea.
National Research Laboratory of Regenerative Sexual Medicine, Department of Urology, Inha University School of Medicine, Incheon, Republic of Korea.
Oncol Rep. 2015 Nov;34(5):2745-51. doi: 10.3892/or.2015.4223. Epub 2015 Aug 24.
Low oxygen or hypoxia can be observed in the central region of solid tumors. Hypoxia is a strong stimulus for new blood vessel formation or angiogenesis, which is essential for tumor growth and progression. Fibroblast growth factor 11 (FGF11) is an intracellular non-secretory FGF whose function has not yet been fully characterized. In the present study, we demonstrated that FGF11 expression is upregulated under hypoxic conditions in human umbilical vein endothelial cells (HUVECs). FGF11 overexpression stimulated capillary-like tube formation, yet did not affect cell migration. Notably, FGF11 markedly increased the levels of tight junction proteins including occludin, zonula occludens-1 (ZO-1) and claudin-5 in HUVECs. The FGF11 promoter contains hypoxia response elements (HREs), and hypoxia-inducible factor-1 (HIF-1) binds to HREs to activate hypoxia-related genes. We demonstrated that hypoxia or HIF-1 expression under normoxic conditions increased the luciferase activity driven by the FGF11 promoter. However, deletion of the HREs from the FGF11 promoter rendered reporter gene activity unresponsive to hypoxia or HIF-1. Taken together, we propose that FGF11 may be involved in the stabilization of capillary-like tube structures associated with angiogenesis and may act as a modulator of hypoxia-induced pathological processes such as tumorigenesis.
在实体瘤的中心区域可观察到低氧或缺氧状态。缺氧是新血管形成或血管生成的强烈刺激因素，而血管生成对于肿瘤的生长和进展至关重要。成纤维细胞生长因子11（FGF11）是一种细胞内非分泌型FGF，其功能尚未完全明确。在本研究中，我们证明在缺氧条件下人脐静脉内皮细胞（HUVECs）中FGF11表达上调。FGF11过表达刺激了毛细血管样管腔的形成，但不影响细胞迁移。值得注意的是，FGF11显著增加了HUVECs中紧密连接蛋白的水平，包括闭合蛋白、紧密连接蛋白1（ZO-1）和Claudin-5。FGF11启动子包含缺氧反应元件（HREs），缺氧诱导因子-1（HIF-1）与HREs结合以激活缺氧相关基因。我们证明在常氧条件下缺氧或HIF-1表达增加了由FGF11启动子驱动的荧光素酶活性。然而，从FGF11启动子中删除HREs使得报告基因活性对缺氧或HIF-1无反应。综上所述，我们提出FGF11可能参与了与血管生成相关的毛细血管样管腔结构的稳定，并可能作为缺氧诱导的病理过程（如肿瘤发生）的调节因子。
