脯氨酰羟化酶1（PHD1 / EGLN2）的表达抑制缺氧诱导因子1α激活并抑制肿瘤的生长。,Cancer Research

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脯氨酰羟化酶1（PHD1 / EGLN2）的表达抑制缺氧诱导因子1α激活并抑制肿瘤的生长。
Cancer Research ( IF 12.5 ) Pub Date : 2003 Dec 15
Erez, Neta, Milyavsky, Michael, Eilam, Raya, Shats, Igor, Goldfinger, Naomi, Rotter, Varda

缺氧应激是实体瘤微环境中的主要选择性压力之一，克服这一限制对于肿瘤的进展至关重要。引起细胞对缺氧反应的关键因素之一是缺氧诱导因子（HIF），这是一种关键的转录因子。HIF-1的α亚基的水平受到脯氨酰羟化酶（PHDs / EGLNs）家族控制的快速降解的调节，其活性取决于氧气的供应。我们的研究表明，mPHD1的异位表达抑制了缺氧模拟药物处理细胞后HIF-1alpha的积累和血管内皮生长因子的分泌。此外，将表达mPHD1的结肠癌细胞注入裸鼠后，肿瘤的生长受到抑制，并且肿瘤生长的抑制与坏死增加和微血管密度显着降低有关。这些数据表明通过激活HIF羟化酶抑制缺氧诱导的HIF-1α激活可以提供一种抑制肿瘤生长和新生血管形成的新治疗策略，并支持基于激活HIF脯氨酰羟化酶的基因转移方法的发展。。

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Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1alpha activation and inhibits tumor growth.

Hypoxic stress is one of the major selective pressures in the microenvironment of solid tumors, and overcoming this restriction is essential for tumor progression. One of the key factors driving the cellular response to lack of oxygen is hypoxia inducible factor (HIF), a key transcriptional factor. The level of the alpha subunit of HIF-1 is regulated by rapid degradation that is controlled by a family of prolyl hydroxylases (PHDs/EGLNs), the activity of which depends on oxygen availability. Our study shows that ectopic expression of mPHD1 suppressed accumulation of HIF-1alpha and secretion of Vascular Endothelial Growth Factor after treatment of cells with a hypoxia-mimetic drug. Furthermore, when colon carcinoma cells expressing mPHD1 were injected into nude mice, tumor growth was inhibited, and the inhibition of tumor growth was correlated with increased necrosis and a striking decrease in microvessel density. These data demonstrate that inhibition of hypoxia-induced activation of HIF-1alpha through activation of HIF-hydroxylase can provide a novel therapeutic strategy for inhibition of tumor growth and neovascularization and support the development of gene transfer approaches based on the activation of HIF-prolyl hydroxylases.

更新日期：2017-01-31

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