α1A-Adrenergic receptor (ADRA1A) signaling signatures as prognostic biomarkers in liver hepatocellular carcinoma: a bioinformatic analysis

Abstract The α 1A -adrenergic receptor, encoded by ADRA1A , couples to heterotrimeric G q/11 proteins, promoting intracellular calcium mobilization and PKC activation. In human hepatocytes, it regulates acute metabolic responses and impacts gene expression. Although fundamental hepatic functions of ADRA1A have been described, its role in hepatocellular carcinoma remains elusive. We hypothesized that ADRA1A expressed in liver cancer tissue is part of a signaling repertoire potentially linked to patient outcomes. We analyzed The Cancer Genome Atlas liver cancer datasets and found ADRA1A gene deletion in 6% of patients and more prolonged survival of patients with high ADRA1A expression. Thus, we aimed to identify ADRA1A -signaling partners equally linked to more prolonged patient survival. Through a rational data mining strategy, based on the identification of the signaling repertoire linked to ADRA1A expression and statistical correlation with patient survival, we identified a transcriptional signature integrated by the adrenoceptor and five candidate signaling companions including two RhoGEFs: FGD4 and FARP2 , a phospholipid phosphatase: PLPP6 , a RabGAP: TBC1D2B , and an RTK adaptor: BAIAP2 . Additionally, highly co-expressed GPCRs such as ACKR2 , DRD1 , ADRA1B , GPR17 , S1PR1 , and GPR182 , and RTKs like KDR and TEK similarly integrated transcriptional signatures with ADRA1A that correlated with more prolonged survival. Most ADRA1A candidate signaling partners were well-co-expressed with hepatocyte markers, suggesting that integrating ADRA1A -associated signaling networks could improve liver cancer patients’ prognosis.