G protein-coupled receptor kinase 2 regulating β2-adrenergic receptor signaling in M2-polarized macrophages contributes to hepatocellular carcinoma progression

Background: beta 2-adrenoceptors (beta 2-ARs) are expressed on the surface of immune cells, including tumor-associated macrophages (TAMs). Previous studies have demonstrated that the expression of beta 2-ARs in hepatocellular carcinoma (HCC) is significantly increased in vitro. However, the role of beta 2-AR in M2-polarized macrophages remains unclear. G protein-coupled receptor kinase 2 (GRK2) can regulate G protein-coupled receptor (GPCR). Previous studies showed that down-regulation of GRK2 in HCC contributes the HCC progression, but it still remains unclear whether the regulation of beta 2-AR in M2-polarized macrophages by GRK2 can promote HCC. Purpose: The present study was designed to investigate the role of activated beta 2-AR in M2-polarized macrophages in the HCC progression and GRK2 regulatory effect, as well as the underlying mechanisms involved. Results: The results demonstrated that the M2-polarized macrophages were increased with HCC progression. In vitro, the activation of beta 2-AR by terbutaline in M2-polarized macrophages elevated the proliferative, migratory and invasive attributes of HCC cells. Furthermore, GRK2 down-regulation in beta 2-AR activated M2-polarized macrophages activated the downstream cyclic adenosine monophosphate (cAMP)/protein kinase A/cAMPresponse element binding protein and cAMP/interleukin-6/signal transducer and the activator of transcription 3 signaling pathways, contributing to the secretion of tumor-associated cytokines, and thus resulting in the promotion of malignant biological behavior in HCC cells. Conclusion: These findings suggest that the regulation of beta 2-AR occurs through the silencing of GRK2 in M2-polarized macrophages, which is conducive to HCC development, through its engagement in the activation of downstream signaling.