The Translation Initiation Factor eIF3i Up-regulates Vascular Endothelial Growth Factor A, Accelerates Cell Proliferation, and Promotes Angiogenesis in Embryonic Development and Tumorigenesis*
The Translation Initiation Factor eIF3i Up-regulates Vascular Endothelial Growth Factor A, Accelerates Cell Proliferation, and Promotes Angiogenesis in Embryonic Development and Tumorigenesis*
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DOI：
10.1074/jbc.m114.571356
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发表时间：
2014-08
期刊：
影响因子：
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通讯作者：
Yike Yuan;Yaguang Zhang;Shaohua Yao;Hua-Shan Shi;Xi Huang;Yu-Hao Li;Yuquan Wei;Shuo Lin
中科院分区：
文献类型：
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作者：
Yike Yuan;Yaguang Zhang;Shaohua Yao;Hua-Shan Shi;Xi Huang;Yu-Hao Li;Yuquan Wei;Shuo Lin
背景：低氧在转录和转录后水平调节VEGFA的表达。结果：缺氧条件下，HIF1a可诱导EIF3i，并控制VEGFA蛋白翻译。结论：eIF3i在正常和肿瘤血管生成过程中调控VEGFA信号转导。意义：我们的数据揭示了VEGFA调节的新机制，eIF3i可以成为抗癌治疗的肿瘤靶点。血管内皮生长因子A(VEGFA)是一种重要的促血管生成因子，可在转录和转录后水平被低氧激活。在低氧条件下，稳定的低氧诱导因子1α(HIF1a)是转录激活VEGFA的关键调控因子。然而，VEGFA表达的转录后调控仍然知之甚少。在此，我们报道了在正常胚胎和肿瘤血管生成中，VEGFA蛋白的表达都需要真核细胞翻译起始因子3i(EIF3i)。EIF3i在斑马鱼胚胎发育的早期和人肝细胞癌组织中动态表达。在肿瘤模型中，eIF3i纯合子突变斑马鱼胚胎表现出严重的血管生成缺陷，而人肝细胞癌细胞缺乏eIF3i诱导的血管生成较少。在低氧条件下，HIF1a蛋白可以与其在eIF3i启动子中的结合序列相互作用，激活eIF3i转录。EIF3i siRNA处理显著抑制了VEGFA的表达，而VEGFA在低氧条件下本应升高。此外，eIF3i基因敲除并没有导致普遍的翻译抑制，而是特别降低了VEGFA mRNAs的翻译效率。综上所述，我们的结果表明，eIF3i是在缺氧条件下由HIF1a诱导的，并通过调节VEGFA蛋白的翻译来调控正常和肿瘤血管的生成。
Background: Hypoxia regulates VEGFA expression at both the transcriptional and post-transcriptional levels. Results: eIf3i is induced by HIF1A under hypoxia and controls VEGFA protein translation. Conclusion: eIF3i controls VEGFA signaling during normal and tumorigenic angiogenesis. Significance: Our data reveal a new mechanism for VEGFA regulation, and eIF3i can be an oncotarget in anticancer therapies. Vascular endothelial growth factor A (VEGFA) is a critical proangiogenic factor that is activated by hypoxia at both the transcriptional and post-transcriptional levels. In hypoxia conditions, stabilized hypoxia-inducible factor 1α (HIF1A) is the key regulator for transcriptional activation of VEGFA. However, the post-transcriptional control of VEGFA expression remains poorly understood. Here, we report that the eukaryotic translation initiation factor 3i (eIF3i) is required for VEGFA protein expression in both normal embryonic and tumorigenic angiogenesis. eIF3i is dynamically expressed in the early stages of zebrafish embryogenesis and in human hepatocellular carcinoma tissues. eIF3i homozygous mutant zebrafish embryos show severe angiogenesis defects and human hepatocellular cancer cells with depletion of eIF3i to induce less angiogenesis in tumor models. Under hypoxia, the HIF1A protein can interact with its binding sequence in the eIF3i promoter and activate eIF3i transcription. The expression of VEGFA, which should rise in hypoxia, is significantly inhibited by eIF3i siRNA treatment. Moreover, eIF3i knockdown did not cause a general translation repression but specifically reduced the translation efficiency of the VEGFA mRNAs. Taken together, our results suggest that eIF3i is induced by HIF1A under hypoxia and controls normal and tumorigenic angiogenesis through regulating VEGFA protein translation.