Garkavtsev Igor, Kozin Sergey V, Chernova Olga, Xu Lei, Winkler Frank, Brown Edward, Barnett Gene H, Jain Rakesh K
Edwin L. Steele Laboratory for Tumour Biology, Department of Radiation Oncology Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Nature. 2004 Mar 18;428(6980):328-32. doi: 10.1038/nature02329.
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. The marked induction of angiogenesis in glioblastomas suggests that it is a necessary part of malignant progression; 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.
神经胶质瘤是中枢神经系统最常见的原发性肿瘤，在美国每年有近15000例被诊断出来，胶质母细胞瘤诊断后的第一年致死率接近80%。胶质母细胞瘤中显著的血管生成诱导表明它是恶性进展的必要部分；然而，脑肿瘤生长和血管生成调节的精确分子机制仍未解决。在此我们报告，一个候选肿瘤抑制基因ING4参与调节脑肿瘤生长和血管生成。与正常人类脑组织相比，ING4在神经胶质瘤中的表达显著降低，且降低程度与肿瘤从低级别到高级别的进展相关。在小鼠中，ING4表达降低的人胶质母细胞瘤U87MG异种移植瘤比对照肿瘤生长明显更快，且血管体积分数更高。我们表明，ING4与核因子NF-κB的p65（RelA）亚基发生物理相互作用，并且ING4通过对NF-κB反应性基因的转录抑制来调节脑肿瘤血管生成。这些结果表明ING4在脑肿瘤发病机制中起重要作用。
