Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region
Oncolytic replication-competent adenovirus suppresses tumor angiogenesis through preserved E1A region
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DOI：
10.1038/sj.cgt.7700902
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发表时间：
2006-03-01
影响因子：
6.4
通讯作者：
Matsuno, S
中科院分区：
文献类型：
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作者：
Saito, Y;Sunamura, M;Matsuno, S
保留正常 E1A 但缺乏 55 kDa E1B 蛋白的腺病毒 (Adv) 优先在 TP53 缺陷的癌细胞（包括胰腺癌细胞系）中复制，导致肿瘤溶瘤。当肿瘤细胞处于缺氧状态时，缺氧诱导因子 1 α (HIF-1 α) 会稳定并被激活，以促进血管内皮生长因子 (VEGF) 等多种基因的转录，但在 E1A 存在的情况下，缺氧诱导的 VEGF mRNA 合成会因 E1A 与 p300 的结合而受到抑制。在这项研究中，我们证明，与感染正常E1A的Adv相比，感染E1A中p300结合位点部分缺失的突变Adv的癌细胞诱导了更高的VEGF表达水平。 E1A 的免疫沉淀研究证实，突变型 E1A 对 p300 的结合能力降低。虽然感染突变型Adv和感染野生型Adv的癌细胞中HIF-1 α mRNA的表达几乎相同，但感染野生型E1A Adv的癌细胞中HIF-1 α蛋白的量低于感染突变型E1A型Adv的癌细胞。在体内，与突变型E1A处理的血管生成相反，野生型E1A显着抑制肿瘤血管生成。这些结果表明，E1A 通过与 p300 结合抑制 VEGF 的产生并抑制肿瘤血管生成，从而通过与 HRE 结合抑制 HIF-1 α 介导的基因转录。这项研究首次证明了具有溶瘤复制能力的 Adv 在抑制肿瘤血管生成方面的作用。
An adenovirus (Adv) retaining normal E1A but lacking the 55 kDa E1B protein replicates preferentially in TP53-deficient cancer cells including pancreatic cancer cell lines, resulting in the oncolysis of the tumor. When tumor cells are exposed to hypoxia, hypoxia-inducible factor-1 alpha (HIF-1 alpha) is stabilized and activated to promote the transcription of several genes such as vascular endothelial growth factor (VEGF), but in the presence of E1A hypoxia-induced VEGF m-RNA synthesis is inhibited by E1A binding to p300. In this study, we demonstrated that the cancer cells infected with a mutant Adv in which the p300 binding site in E1A was partially deleted induced a higher expression level of VEGF as compared to those of Adv with normal E1A. An immunoprecipitation study for E1A confirmed that mutant E1A had a reduced binding capacity for p300. Although the expressions of HIF-1 alpha m-RNA were almost the same in both cancer cells infected with the mutant Adv and those with the wild Adv, the amount of HIF-1 alpha protein in cancer cells infected with the wild E1A Adv was lower than in those infected with the mutant E1A type Adv. In vivo, in contrast to the angiogenesis treated with mutant E1A, wild-E1A inhibited tumor angiogenesis significantly. These results suggested that E1A suppressed the production of VEGF and inhibited tumor angiogenesis by binding with p300, resulting in the inhibition of the HIF-1 alpha-mediated transcription of genes through binding to HRE. This study demonstrates, for the first time, the effect of an oncolytic replication-competent Adv in inhibiting tumor angiogenesis.