Yuan, Y., Zhang, Y., Yao, S., Shi, H., Huang, X., Li, Y., Wei, Y., Lin, S. (2014) The translation initiation factor Eif3i upregulates vascular endothelial growth factor A, accelerates cell proliferation, and promotes angiogenesis in embryonic development and tumorigenesis. The Journal of biological chemistry. 289(41):28310-23.
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 (Hif1α) 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 early stage 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 induce less angiogenesis in tumor models. Under hypoxia, the Hif1α protein can interact with its binding sequence in Eif3i promoter and activates Eif3i transcription. The expression of Vegfa, which ought to rise in hypoxia, is significantly inhibited by Eif3i siRNAs treatment. Besides, 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 Hif1α under hypoxia and controls normal and tumorigenic angiogenesis through regulating Vegfa protein translation.