Abstract
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.
Highlights
Hypoxia regulates Vascular endothelial growth factor A (VEGFA) expression at both the transcriptional and post-transcriptional levels
We report that the eukaryotic translation initiation factor 3i 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
Because eIF3i expression is more sensitive to hypoxia conditions and the eIF3i promoter region that contains hypoxia-responsive element (HRE) is very conserved during evolution, we focused our study on elucidating whether eIF3i is a direct target of HIF1A
Summary
Hypoxia regulates VEGFA expression at both the transcriptional and post-transcriptional levels. EIF3i knockdown did not cause a general translation repression but 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. Our results suggest that eIF3i is induced by HIF1A under hypoxia and controls normal and tumorigenic angiogenesis through regulating VEGFA protein translation Hypoxic conditions can enhance eIF3i expression, and HIF1A directly regulates eIF3i transcription by binding to the HRE in the eIF3i promoter Taken together, these findings demonstrate that eIF3i is critical for VEGFA protein expression in embryonic and tumorigenic development, offering a regulatory mechanism for eIF3i expression in cancer cells
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