Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Ribera J

PROVIDER: S-EPMC8519955 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Ribera Jordi J Portolés Irene I Córdoba-Jover Bernat B Rodríguez-Vita Juan J Casals Gregori G González-de la Presa Bernardino B Graupera Mariona M Solsona-Vilarrasa Estel E Garcia-Ruiz Carmen C Fernández-Checa José C JC Soria Guadalupe G Tudela Raúl R Esteve-Codina Anna A Espadas Guadalupe G Sabidó Eduard E Jiménez Wladimiro W Sessa William C WC Morales-Ruiz Manuel M

Communications biology 20211015 1

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<sup>-/-</sup> zebrafish also showed downregulation of VEGF-C and reduced formation of lymphatic structures during development. DHX15<sup>+/-</sup> mice depicted lower vascular density and impaired lymphatic function postnatally. RNAseq and pro ...[more]

PMID: 34654883

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Project description:DHX15 is an ATP-dependent RNA helicase involved in pre-mRNA splicing. We have recently reported that DHX15 is a downstream substrate for Akt1, which plays a significant role in vascular biology. Therefore, we aimed to explore the regulatory function of DHX15 over the vasculature, and the endothelial cell biology in different contexts: development, metabolism, ischemia and tumor growth. Methods: Deficient DHX15 mice and zebrafish were generated using transcription activator-like effector nuclease (TALEN) and Crispr/cas9 gene edition. Lymphatic functionality was evaluated by lymphangiography and magnetic resonance imaging. Mouse-induced tumor and metastasis model were generated by injection of syngeneic LLC1 tumor cells. DHX15 gene silencing in mouse liver endothelial cells (LEC) was performed by the lentiviral transduction of shRNA (Dharmacon). The changes in the transcriptome and the proteome resulting from the shRNA transduction were investigated by RNAseq and mass spectrometry, respectively. Results: Homozygous DHX15 gene deficiency was lethal in mouse and zebrafish embryos. DHX15-/- zebrafish also showed an undeveloped parachordal line, which leads to the formation of lymphatic structures in the trunk during the development. DHX15+/- mice and zebrafish were viable, although DHX15+/- gene deficiency triggered lower vascular network density and impaired lymphatic function postnatally in mice. Whole transcriptome and proteome analysis of DHX15 silenced LEC revealed differential expression of enzymes involved in the glycolysis and the gluconeogenesis pathways. The functional validation of these results demonstrated an uncoupling of the glycolysis with the oxidation of pyruvate into the mitochondria and lower activity of the Complex I in the mitochondrial membrane, resulting in lower cellular ATP production. Noteworthy, heterozygous DHX15 deficiency partially inhibited primary tumor growth and reduced lung metastasis after injection of syngeneic LLC1 tumor cells, compared to wild-type mice

Dataset Information

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

Publications

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

Similar Datasets

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