miR-486-5p suppresses autophagy in hepatocellular carcinoma via activation of the AKT/mTOR signalling pathway

Autophagy is controlled by a complex signalling network and is closely linked to the initiation and progression of hepatocellular carcinoma (HCC). However, how microRNAs (miRNAs) regulate autophagy in HCC remains incompletely understood. In this study, we identified microRNA-486-5p (miR-486-5p) as a tumour-associated microRNA that is enriched in circulating exosomes derived from patients with HCC. Elevated miR-486-5p promoted proliferation and suppressed apoptosis in HCC cell lines under stress conditions. Mechanistically, miR-486-5p directly targets the 3' untranslated region of the phosphatase and tensin homologue (PTEN) gene, thereby decreasing the production of the PTEN protein and consequently leading to the activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway. This phenomenon was accompanied by the inhibitory phosphorylation of unc-51 like autophagy-activating kinase 1 (ULK1), which resulted in impaired autophagy. The pharmacological inhibition of AKT or mTOR led to the restoration of autophagy and the attenuation of miR-486-5p-driven growth and survival advantages. Furthermore, the transcription factor MYB was found to bind the promoter of ankyrin-1 (ANK1), the host gene of miR-486-5p, and to drive its expression. In an orthotopic liver tumour model, the liver-targeted delivery of miR-486-5p accelerated tumour expansion, an effect that was reversed by AKT or mTOR blockade. Collectively, these findings delineate a MYB/miR-486-5p/PTEN/AKT/mTOR signalling axis that constrains autophagy to facilitate HCC progression, suggesting potential avenues for biomarker development and therapeutic intervention.