ADAR1p110 promotes hepatocellular carcinoma metastasis via the miR-451a/TUBA1A axis

ADAR1 is overexpressed in hepatocellular carcinoma (HCC) and has been linked to poor prognosis, metastasis, and recurrence; however, its precise functions and underlying mechanisms, particularly in the context of metastasis, remain inadequately elucidated. This study seeks to elucidate the functions and underlying mechanisms of the most abundantly expressed isoform of ADAR1, ADAR1p110, in the setting of HCC metastasis. In this study, hepatocyte-specific ADAR1p110 knock-in mice and engineered HCC cell lines were utilized to investigate the function of ADAR1p110 in vivo and in vitro. Genome sequencing, transcriptome sequencing, microRNA sequencing, RNA immunoprecipitation qPCR (RIP-qPCR), and RNA pull-down assays were performed to elucidate the mechanism of ADAR1p110 in HCC. We demonstrated that ADAR1p110 overexpression promotes HCC metastasis by improving the motility of HCC cells. Mechanistically, ADAR1p110 overexpression increases TUBA1A expression, which plays a crucial role in regulating HCC cell motility. At the molecular level, ADAR1p110 suppresses miR-451a biogenesis by competitively binding to pri-miR-451a, thereby preventing its cleavage by the Drosha/DGCR8 complex. Furthermore, we confirmed that TUBA1A is a direct downstream target of miR-451a.