Hypoxia-induced HIF1α activation regulates small extracellular vesicle release in human embryonic kidney cells

Muñiz-García, Ana, Romero, Montserrat, Falcόn-Perez, Juan Manuel, Murray, Patricia, Zorzano, Antonio and Mora, Silvia
(2022) Hypoxia-induced HIF1α activation regulates small extracellular vesicle release in human embryonic kidney cells. Scientific Reports, 12 (1). 1443-.

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<jats:title>Abstract</jats:title><jats:p>Extracellular vesicles (EVs) are membrane enclosures released by eukaryotic cells that carry bioactive molecules and serve to modulate biological responses in recipient cells. Both increased EV release and altered EV composition are associated with the development and progression of many pathologies including cancer. Hypoxia, a feature of rapidly growing solid tumours, increases the release of EVs. However, the molecular mechanisms remain unknown. The hypoxia inducible factors (HIFs) are transcription factors that act as major regulators of the cellular adaptations to hypoxia. Here, we investigated the requirement of HIF pathway activation for EV release in Human Embryonic Kidney Cells (HEK293). Time course experiments showed that EV release increased concomitantly with sustained HIF1α and HIF2α activation following the onset of hypoxia. shRNA mediated knock-down of HIF1α but not HIF2α abrogated the effect of hypoxia on EV release, suggesting HIF1α is involved in this process. However, stabilization of HIF proteins in normoxic conditions through: (i) heterologous expression of oxygen insensitive HIF1α or HIF2α mutants in normoxic cells or (ii) chemical inhibition of the prolyl hydroxylase 2 (PHD2) repressor protein, did not increase EV release, suggesting HIF activation alone is not sufficient for this process. Our findings suggest HIF1α plays an important role in the regulation of EV release during hypoxia in HEK293 cells, however other hypoxia triggered mechanisms likely contribute as stabilization of HIF1α alone in normoxia is not sufficient for EV release.</jats:p>

Item Type: Article
Uncontrolled Keywords: Kidney, Epithelial Cells, Humans, Cell Hypoxia, Basic Helix-Loop-Helix Transcription Factors, Hypoxia-Inducible Factor 1, alpha Subunit, Embryo, Mammalian, Gene Knockdown Techniques, HEK293 Cells, Extracellular Vesicles
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 14 Feb 2022 09:12
Last Modified: 18 Jan 2023 21:12
DOI: 10.1038/s41598-022-05161-7
Open Access URL: https://www.nature.com/articles/s41598-022-05161-7
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3148859