Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression.
Oncogenic transformation and hypoxia synergistically act to modulate vascular endothelial growth factor expression.
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发表时间：
1996-08
期刊：
影响因子：
11.2
通讯作者：
N. Mazure;E. Chen;Patricia Yeh;K. Laderoute;A. Giaccia
中科院分区：
文献类型：
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作者：
N. Mazure;E. Chen;Patricia Yeh;K. Laderoute;A. Giaccia
缺氧可以选择已经失去凋亡潜力的细胞，从而使它们对不利条件具有抵抗力。然而，当暴露于低氧条件时，凋亡敏感性降低的转化细胞的长期存活将需要激活其血管生成程序以补偿不足的氧气供应。在这份报告中，我们表明，活性（致癌Ha-ras，无论是组成性或短暂的，增强诱导血管生成的有丝分裂原，血管内皮生长因子（VEGF），缺氧。VEGF启动子5'侧翼区的分析表明，当暴露于缺氧时，HIF-1样序列促进Ha-ras转化细胞中报告基因活性增加15倍，而同一位点的突变完全抑制VEGF诱导。在低氧条件下，VEGF诱导在表达Ha-ras（RasN 17）的突变抑制等位基因的细胞中被抑制，表明Ras在调节VEGF活性中的直接作用。我们认为Ras转化细胞中的血管生成开关可能是通过VEGF诱导的肿瘤微环境在生理上促进的。
Hypoxia can select for cells that have lost their apoptotic potential, thereby making them resistant to adverse conditions. However, long-term survival of transformed cells which have diminished apoptotic sensitivity when exposed to low oxygen conditions would require the activation of their angiogenic program to compensate for an insufficient oxygen supply. In this report, we show that the activity (of oncogenic Ha-ras, either constitutively or transiently, enhances the induction of the angiogenic mitogen, vascular endothelial growth factor (VEGF), by hypoxia. Analysis of the 5' flanking region of the VEGF promoter indicates that a HIF-1-like sequence is to promote a 15-fold increase in reporter gene activity in Ha-ras-transformed cells when exposed to hypoxia, whereas mutations in the same site totally inhibited VEGF induction. Under low oxygen conditions, VEGF induction is inhibited in cells expressing a mutant inhibitory allele of Ha-ras (RasN17), indicating a direct role for Ras in modulating VEGF activity. We propose that the angiogenic switch in Ras-transformed cells may be physiologically promoted by the tumor microenvironment through VEGF induction.