EEF1A2 promotes HIF1A mediated breast cancer angiogenesis in normoxia and participates in a positive feedback loop with HIF1A in hypoxia

• Published in: British journal of cancer 2024-02, Vol.130 (2), p.184-200
• Main Authors: Patel, Saket Awadhesbhai, Hassan, Md. Khurshidul, Naik, Monali, Mohapatra, Nachiketa, Balan, Poornima, Korrapati, Purna Sai, Dixit, Manjusha
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 631/67/1347; 631/67/2328; AKT protein; Angiogenesis; Aorta; Biomedical and Life Sciences; Biomedicine; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer Research; Cancer therapies; Cell migration; Chorioallantoic membrane; Drug Resistance; Endothelial cells; Endothelial Cells - metabolism; Epidemiology; Feedback; Female; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Molecular Medicine; Myc protein; Oncology; Peptide Elongation Factor 1 - genetics; Peptide Elongation Factor 1 - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Solid tumors; TOR protein; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Wound healing
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/s41416-023-02509-2

Background The eukaryotic elongation factor, EEF1A2, has been identified as an oncogene in various solid tumors. Here, we have identified a novel function of EEF1A2 in angiogenesis. Methods Chick chorioallantoic membrane, tubulogenesis, aortic ring, Matrigel plug, and skin wound healing assays established EEF1A2’s role in angiogenesis. Result Higher EEF1A2 levels in breast cancer cells enhanced cell growth, movement, blood vessel function, and tubule formation in HUVECs, as confirmed by ex-ovo and in-vivo tests. The overexpression of EEF1A2 could be counteracted by Plitidepsin. Under normoxic conditions, EEF1A2 triggered HIF1A expression via ERK-Myc and mTOR signaling in TNBC and ER/PR positive cells. Hypoxia induced the expression of EEF1A2, leading to a positive feedback loop between EEF1A2 and HIF1A. Luciferase assay and EMSA confirmed HIF1A binding on the EEF1A2 promoter, which induced its transcription. RT-PCR and polysome profiling validated that EEF1A2 affected VEGF transcription and translation positively. This led to increased VEGF release from breast cancer cells, activating ERK and PI3K-AKT signaling in endothelial cells. Breast cancer tissues with elevated EEF1A2 showed higher microvessel density. Conclusion EEF1A2 exhibits angiogenic potential in both normoxic and hypoxic conditions, underscoring its dual role in promoting EMT and angiogenesis, rendering it a promising target for cancer therapy.