CircFOXK2 Promotes Hepatocellular Carcinoma Progression and Leads a Poor Clinical Prognosis via Regulating the Warburg Effect

Abstract

Abstract Background: The Warburg effect is essential for tumor progression causing poor clinical outcomes in patients with hepatocellular carcinoma (HCC). Circular RNAs (circRNAs) have emerged as important regulators for HCC. However, limited circRNAs involved in the Warburg effect of HCC have been investigated. Herein, we aimed to explore the contribution of circFOXK2 to the reprogramming of glucose metabolism of HCC. Methods: Divergent primers were constructed to identify 14 circRNAs originating from FOXK2 gene followed by investigating their differential expression between HCC and the adjacent normal tissues (ANTs), and circFOXK2 (hsa_circ_0000817) was screened for further research. Next, the clinical significance of circFOXK2 was evaluated, coupled with evaluating its onco-promoting activity and the affection to the Warburg effect in both HCC cell lines and animal xenografts. Finally, the molecular mechanisms underlying circFOXK2 regulating the Warburg effect of HCC were explored. Results: CircFOXK2 was aberrantly upregulation in HCC tissues, and its expression was positively correlated with poor clinical outcomes in patients receiving radical hepatectomy. Silenced circFOXK2 remarkably suppressed the progression of HCC both in vitro and in vivo. Mechanistically, circFOXK2 could not only encode a novel protein, FOXK2-142aa, to promote LDHA phosphorylation but also regulate miR-484/Fis1 pathway to lead to mitochondrial fission, which activates the Warburg effect in HCC. Conclusions: CircFOXK2, a prognostic biomarker of the disease, exerts critical roles in promoting the Warburg effect through its roles in protein-encoding and miRNA sponges that lead to tumor progression, indicating that circFOXK2 may serve as a potential therapeutic target for patients with HCC.