ATPase Inhibitory Factor 1 Drives Mitochondrial Energy Metabolic Reprogramming to Promote HCC Vasculogenic Mimicry via the ESR1/miR-20a-3p/GNAZ Pathway

Vasculogenic mimicry (VM) is a microcirculation pattern that has a crucial effect on hepatocellular carcinoma (HCC) metastasis. In this study, leveraging the GeneCard and The Cancer Genome Atlas databases, we identified ATPase inhibitory factor 1 (IF1) as a potential regulator of VM formation. Our research findings indicate that IF1 can promote HCC cell tube formation in vitro and enhance HCC VM and lung metastasis in vivo. Transcriptome sequencing combined with in vivo experiments revealed that IF1 knockdown elevates miR-20a-3p expression. Lentivirus-mediated miR-20a-3p overexpression reversed IF1-induced VM. Dual-luciferase reporter gene assays showed that estrogen receptor 1 (ESR1) acts as a transcription factor of the miR-20a-3p precursor. Further mechanistic studies revealed that excessive reactive oxygen species accumulation caused by IF1-induced mitochondrial metabolic reprogramming can inhibit ESR1 expression by promoting DNA methylation of its promoter. G protein subunit alpha Z (GNAZ), a miR-20a-3p target protein, can promote VM by phosphorylating components of the ERK pathway. Collectively, these results delineate a novel IF1/ESR1/miR-20a-3p/GNAZ axis in HCC VM and metastasis, providing potential therapeutic targets.