Loss of NDUFS1 promotes gastric cancer progression by activating the mitochondrial ROS-HIF1alpha-FBLN5 signaling pathway
Menée à l'aide de lignées cellulaires, d'un modèle murin ainsi que d'échantillons tumoraux et d'échantillons de tissus adjacents provenant de patients atteints d'un cancer gastrique, cette étude met en évidence un mécanisme par lequel la perte de l'expression de la sous-unité NDUFS1 de la NADH-ubiquinone oxydoréductase favorise la progression tumorale en activant la voie de signalisation mitochondriale ROS-HIF1alpha
Background : Recent studies suggested that NDUFS1 has an important role in human cancers; however, the effects of NDUFS1 on gastric cancer (GC) are still not fully understood. Methods : We confirmed that NDUFS1 is downregulated in GC cells through western blot immunohistochemistry and bioinformation analysis. The effect of NDUFS1 on GC was studied by CCK-8, colony formation, transwell assay in vitro and Mouse xenograft assay in vivo. Expression and subcellular localization of NDUFS1 and the content of mitochondrial reactive oxygen species (mROS) was observed by confocal reflectance microscopy. Results : Reduced expression of NDUFS1 was found in GC tissues and cell lines. Also, NDUFS1 overexpression inhibited GC cell proliferation, migration, and invasion in vitro as well as growth and metastasis in vivo. Mechanistically, NDUFS1 reduction led to the activation of the mROS-hypoxia-inducible factor 1
α (HIF1α) signaling pathway. We further clarified that NDUFS1 reduction upregulated the expression of fibulin 5 (FBLN5), a transcriptional target of HIF1α, through activation of mROS-HIF1α signaling in GC cells. Conclusions
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The results of this study indicate that NDUFS1 downregulation promotes GC progression by activating an mROS-HIF1α-FBLN5 signaling pathway.