The loss of DHX15 impairs endothelial energy metabolism, lymphatic drainage and tumor metastasis in mice

• Published in: Communications biology Vol. 4; no. 1; p. 1192
• Main Authors: Ribera, Jordi, Portolés, Irene, Córdoba-Jover, Bernat, Rodríguez-Vita, Juan, Casals, Gregori, González-de la Presa, Bernardino, Graupera, Mariona, Solsona-Vilarrasa, Estel, Garcia-Ruiz, Carmen, Fernández-Checa, José C., Soria, Guadalupe, Tudela, Raúl, Esteve-Codina, Anna, Espadas, Guadalupe, Sabidó, Eduard, Jiménez, Wladimiro, Sessa, William C., Morales-Ruiz, Manuel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15-10-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/51; 42/41; 42/44; 42/89; 59/57; 631/337/1645/1792; 631/80/86; 64/110; 64/116; 64/60; 82/29; 82/58; 82/80; 96/1; 96/106; 96/109; 96/31; 96/34; 96/47; 96/95; AKT1 protein; Animal models; Animals; Biology; Biomedical and Life Sciences; Danio rerio; DNA helicase; Electron transport chain; Embryo, Mammalian - metabolism; Embryo, Nonmammalian - embryology; Embryo, Nonmammalian - metabolism; Embryos; Endothelial cells; Endothelium - metabolism; Energy Metabolism; Life Sciences; Lymphatic drainage; Lymphatic System - pathology; Metabolism; Metastases; Metastasis; Mice; Mice, Transgenic - embryology; Mitochondria; Neoplasm Metastasis; Neoplasms; Oxygen consumption; Proteomes; RNA helicase; RNA Helicases - deficiency; Tumor cells; Vascular endothelial growth factor; Zebrafish - embryology
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02722-w

DHX15 is a downstream substrate for Akt1, which is involved in key cellular processes affecting vascular biology. Here, we explored the vascular regulatory function of DHX15. Homozygous
DHX15
gene deficiency was lethal in mouse and zebrafish embryos. DHX15
—/—
zebrafish also showed downregulation of VEGF-C and reduced formation of lymphatic structures during development.
DHX15
+/−
mice depicted lower vascular density and impaired lymphatic function postnatally. RNAseq and proteome analysis of DHX15 silenced endothelial cells revealed differential expression of genes involved in the metabolism of ATP biosynthesis. The validation of these results demonstrated a lower activity of the Complex I in the mitochondrial membrane of endothelial cells, resulting in lower intracellular ATP production and lower oxygen consumption. After injection of syngeneic LLC1 tumor cells, DHX15
+/−
mice showed partially inhibited primary tumor growth and reduced lung metastasis. Our results revealed an important role of DHX15 in vascular physiology and pave a new way to explore its potential use as a therapeutical target for metastasis treatment.
Jordi Ribera et al. use zebrafish and mouse models to examine the role of the ATP-dependent RNA helicase, DHX15, in vascular health. Their results suggest that DHX15 depletion can cause vascular defects in vertebrates, potentially by impacting endothelial ATP production.