The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis
The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis
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DOI：
10.1038/nature02329
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发表时间：
2004-03-18
期刊：
影响因子：
64.8
通讯作者：
Jain, RK
中科院分区：
文献类型：
--
作者：
Garkavtsev, I;Kozin, SV;Jain, RK
胶质瘤是中枢神经系统最常见的原发性肿瘤，在美国每年诊断出近15，000例，并且在胶质母细胞瘤诊断的第一年内死亡率接近80%（1）。胶质母细胞瘤中血管生成的显著诱导表明其是恶性进展的必要部分（2）;然而，调节脑肿瘤生长和血管生成的精确分子机制仍未解决。在这里，我们报告说，一个候选的肿瘤抑制基因，ING 4，参与调节脑肿瘤的生长和血管生成。与正常人脑组织相比，胶质瘤中ING 4的表达显著降低，并且降低的程度与从较低级别到较高级别的肿瘤的进展相关。在小鼠中，具有降低的ING 4表达的人胶质母细胞瘤U87 MG的异种移植物生长显著更快，并且具有比对照肿瘤更高的血管体积分数。我们发现ING 4与核因子NF-κ B的p65（RelA）亚基相互作用，并且ING 4通过NF-κ B反应基因的转录抑制来调节脑肿瘤血管生成。这些结果表明ING 4在脑肿瘤发病机制中具有重要作用。
Gliomas are the most common primary tumours of the central nervous system, with nearly 15,000 diagnosed annually in the United States and a lethality approaching 80% within the first year of glioblastoma diagnosis(1). The marked induction of angiogenesis in glioblastomas suggests that it is a necessary part of malignant progression(2); however, the precise molecular mechanisms underlying the regulation of brain tumour growth and angiogenesis remain unresolved. Here we report that a candidate tumour suppressor gene, ING4, is involved in regulating brain tumour growth and angiogenesis. Expression of ING4 is significantly reduced in gliomas as compared with normal human brain tissue, and the extent of reduction correlates with the progression from lower to higher grades of tumours. In mice, xenografts of human glioblastoma U87MG, which has decreased expression of ING4, grow significantly faster and have higher vascular volume fractions than control tumours. We show that ING4 physically interacts with p65 ( RelA) subunit of nuclear factor NF-kappaB, and that ING4 regulates brain tumour angiogenesis through transcriptional repression of NF-kappaB-responsive genes. These results indicate that ING4 has an important role in brain tumour pathogenesis.