β-
Adrenergic receptor (β-AR) signalling is strongly associated with tumour progression by the coupling of β-ARs with either a
G protein or β-
arrestin; however, the related mechanism underlying
hepatocellular carcinoma (HCC)
metastasis is not clear. Here, we reveal that the
transcription factor Y-box binding protein 1 (YB-1) interacts with β2-adrenergic receptor (β2-AR) following stimulation with the agonist
isoproterenol (ISO). Clinicopathological analysis demonstrated that β2-AR is significantly correlated with YB-1, which favours the progression of HCC. The binding of YB-1 with β2-AR resulted in YB-1 phosphorylation at
serine 102 (S102) via the β-arrestin-1-dependent activation of the PI3K/AKT pathway, followed by the translocation of YB-1 to the nucleus to carry out its tumour-related function. β2-AR-mediated activation of YB-1 facilitated epithelial-to-mesenchymal transition (EMT) and HCC
metastasis. The interference of YB-1 expression significantly attenuated liver tumour
metastasis induced by chronic stress. Analysis of the transcriptional profile and
chromatin immunoprecipitation (ChIP) identified β-
catenin as a crucial target of YB-1. Our results unveiled a novel β2-AR-mediated regulatory axis in HCC
metastasis that might be helpful for the development of HCC
therapeutics.