Liang Chen, Guo Shiwen, Yang Ling
Department of Neurosurgery, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Department of Aeromedical Physical Examination, Xi'an Civil Aviation Hospital, Xi'an, Shaanxi 710082, P.R. China.
Mol Med Rep. 2014 Nov;10(5):2713-9. doi: 10.3892/mmr.2014.2543. Epub 2014 Sep 5.
All‑trans retinoic acid (ATRA) is one of the most potent inducers of differentiation and is capable of inducing differentiation and apoptosis in glioma cells. However, the effect of ATRA on glioma angiogenesis is yet to be elucidated. The present study investigated the effects of ATRA on the expression of vascular endothelial growth factor (VEGF) and hypoxia‑inducible factor‑1α (HIF‑1α) in various glioma cell lines under normoxia and hypoxia. The effect of ATRA on angiogenesis in a rat intracerebral glioma model was also investigated, with the aim of revealing the effect of ATRA on glioma angiogenesis. In the present study, U‑87 MG and SHG44 glioma cells were treated with ATRA at various concentrations (0, 5, 10, 20 and 40 µmol/l) under normoxia or hypoxia. Quantitative polymerase chain reaction and western blot analysis were used to investigate VEGF and HIF‑1α mRNA and protein expression, respectively. An intracerebral glioma model was generated using intracerebral implantation of C6 glioma cells into rats. Tumor‑bearing rats were treated with ATRA at different doses (0, 5 and 10 mg/kg/day) for two weeks, and immunohistochemical assays were performed to detect the cluster of differentiation 34‑positive cells in order to evaluate the microvessel density (MVD) in each group. Following ATRA treatment, the expression of VEGF and HIF‑1α was found to vary among the different concentration groups. In the glioma cells in the lower concentration groups (5 and 10 µmol/l ATRA), a significant increase in VEGF and HIF‑1α expression was observed. Conversely, a significant decrease in VEGF and HIF‑1α expression was found in the glioma cells in the high ATRA concentration group (40 µmol/l), compared with that in the cells in the control group. Furthermore, in the rat intracerebral glioma model, ATRA decreased glioma MVD, particularly in the high‑dose group (10 mg/kg/day), compared with the control group. These results suggest that ATRA may exhibit a dose‑dependent effect on glioma angiogenesis and may inhibit glioma angiogenesis in vivo.
全反式维甲酸（ATRA）是最有效的分化诱导剂之一，能够诱导胶质瘤细胞分化和凋亡。然而，ATRA对胶质瘤血管生成的影响尚待阐明。本研究调查了常氧和缺氧条件下ATRA对各种胶质瘤细胞系中血管内皮生长因子（VEGF）和缺氧诱导因子-1α（HIF-1α）表达的影响。还研究了ATRA对大鼠脑内胶质瘤模型血管生成的影响，旨在揭示ATRA对胶质瘤血管生成的作用。在本研究中，U-87 MG和SHG44胶质瘤细胞在常氧或缺氧条件下用不同浓度（0、5、10、20和40 μmol/L）的ATRA处理。分别采用定量聚合酶链反应和蛋白质印迹分析来研究VEGF和HIF-1α的mRNA和蛋白表达。通过将C6胶质瘤细胞脑内植入大鼠建立脑内胶质瘤模型。荷瘤大鼠用不同剂量（0、5和10 mg/kg/天）的ATRA处理两周，进行免疫组织化学检测以检测分化簇34阳性细胞，从而评估每组的微血管密度（MVD）。ATRA处理后，发现不同浓度组中VEGF和HIF-1α的表达有所不同。在较低浓度组（5和10 μmol/L ATRA）的胶质瘤细胞中，观察到VEGF和HIF-1α表达显著增加。相反，与对照组细胞相比，高ATRA浓度组（40 μmol/L）的胶质瘤细胞中VEGF和HIF-1α表达显著降低。此外，在大鼠脑内胶质瘤模型中，与对照组相比，ATRA降低了胶质瘤MVD，尤其是高剂量组（10 mg/kg/天）。这些结果表明，ATRA可能对胶质瘤血管生成具有剂量依赖性作用，并可能在体内抑制胶质瘤血管生成。
