CircMFN2/miR-361-3p/ELK1 feedback loop promotes glutaminolysis and the progression of hepatocellular carcinoma

Abstract

Current evidence indicates that circRNAs are involved in the development of multiple malignancies including hepatocellular carcinoma (HCC). However, the specific functions of circRNAs in HCC metabolism and progression and their underlying regulatory mechanisms remain unclear. We have identified a novel circRNA circMFN2, by bioinformatics analysis of circRNA microarray data from the GEO database. The levels of circMFN2 were assessed in HCC cell lines and tissues, and its clinical relevance was assessed. The effect of circMFN2 on HCC cells was evaluated in vitro and in vivo. The effect of ELK1 on glutaminolysis and HCC progression was also explored. Patients with HCC and high circMFN2 expression exhibited worse survival outcomes. Functionally, downregulation of circMFN2 repressed the proliferation, invasion, and migration of HCC cells in vitro, whereas ectopic expression of circMFN2 had the opposite effects. The effects of tumor enhancement by circMFN2 on HCC were confirmed by in vivo experiments. Mechanistically, circMFN2 acted as a sponge for miR-361-3p, leading to the upregulation of its target ELK1, whereas ELK1 was enriched in the MFN2 promoter to enhance the transcription and expression of MFN2, indirectly leading to the upregulation of circMFN2. Additionally, we found that circMFN2 promotes glutaminolysis in HCC by increasing ELK1 phosphorylation. We concluded that circMFN2 facilitates HCC progression via a circMFN2/miR-361-3p/ELK1 feedback loop, which promotes glutaminolysis mediated by the upregulation of phosphorylated ELK1. Therefore, circMFN2 not only serves as a potential prognostic indicator, but it could also serve as a therapeutic target for HCC. Further studies are warranted.