A novel beta 2-AR/YB-1/beta-catenin axis mediates chronic stress-associated metastasis in hepatocellular carcinoma

beta-Adrenergic receptor (beta-AR) signalling is strongly associated with tumour progression by the coupling of beta-ARs with either a G protein or beta-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 beta 2-adrenergic receptor (beta 2-AR) following stimulation with the agonist isoproterenol (ISO). Clinicopathological analysis demonstrated that beta 2-AR is significantly correlated with YB-1, which favours the progression of HCC. The binding of YB-1 with beta 2-AR resulted in YB-1 phosphorylation at serine 102 (S102) via the beta-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. beta 2-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 beta-catenin as a crucial target of YB-1. Our results unveiled a novel beta 2-AR-mediated regulatory axis in HCC metastasis that might be helpful for the development of HCC therapeutics.