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

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.
This study was supported by grants from MCIN/AEI/10.13039/501100011033 (SAF2016-75358-R and PDI2019-105502RB-100 to MM-R, SAF2017-85877R, PID2019-111669RB-100, PID2020-115055RB-I00). CIBERehd, CIBERonc and CIBERbbn are financed by the Instituto de Salud Carlos III. I.P. was recipient of a predoctoral fellowship supported by MCIN/AEI/10.13039/501100011033 y FSE “El FSE invierte en tu futuro” (BES-2017-080823). A.E-.C. is funded by ISCIII of the MINECO (reference PT17/0009/0019) and co-financed by FEDER. J.R-.V. was a recipient of a BIOTRACK Postdoctoral Fellowship supported by the European Community’s Seventh Framework Programme and the MINECO (Contract 229673). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. The center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208, and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595). The authors would like to thank Drs. Simone Calzolari, Rafael Miñana and Javier Terriente from ZeClinics for their helpful collaboration with the zebrafish model generation and experimentation.