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.

β-肾上腺素能受体 (β-AR) 信号通过将 β-AR 与 G 蛋白或 β-抑制蛋白偶联而与肿瘤进展密切相关；然而，肝细胞癌（HCC）转移的相关机制尚不清楚。在这里，我们揭示了转录因子 Y-box 结合蛋白 1 (YB-1) 在激动剂异丙肾上腺素 (ISO) 刺激后与 β2-肾上腺素能受体 (β2-AR) 相互作用。临床病理分析表明β2-AR与YB-1显着相关，有利于HCC的进展。YB-1 与 β2-AR 的结合导致 YB-1 在丝氨酸 102（S102）处磷酸化，通过 β-arrestin-1 依赖性激活 PI3K/AKT 途径，随后 YB-1 易位至细胞核以发挥其与肿瘤相关的功能。β2-AR 介导的 YB-1 激活促进了上皮间质转化 (EMT) 和 HCC 转移。YB-1表达的干扰显着减弱了慢性应激诱导的肝肿瘤转移。转录谱和染色质免疫沉淀 (ChIP) 的分析确定 β-连环蛋白是 YB-1 的关键靶点。我们的研究结果揭示了一种新的 β2-AR 介导的 HCC 转移调节轴，可能有助于 HCC 疗法的发展。