Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
German Cancer Research Center, Heidelberg, Germany.
Commun Biol. 2021 Oct 15;4(1):1192. 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.
DHX15 是 Akt1 的下游底物，后者参与影响血管生物学的关键细胞过程。在这里，我们探索了 DHX15 的血管调节功能。DHX15 基因在小鼠和斑马鱼胚胎中的纯合缺失是致命的。DHX15 斑马鱼在发育过程中也表现出 VEGF-C 的下调和淋巴管结构形成减少。DHX15 小鼠在出生后表现出较低的血管密度和受损的淋巴管功能。DHX15 沉默的内皮细胞的 RNAseq 和蛋白质组分析显示，参与 ATP 生物合成代谢的基因表达差异。这些结果的验证表明内皮细胞线粒体膜中复合物 I 的活性降低，导致细胞内 ATP 产生减少和耗氧量降低。在注射同源 LLC1 肿瘤细胞后，DHX15 小鼠显示原发性肿瘤生长部分受到抑制，肺转移减少。我们的结果揭示了 DHX15 在血管生理学中的重要作用，并为探索其作为转移治疗的治疗靶点的潜在用途开辟了新途径。
