As shown by the schematic in Fig. 7, inflammatory mediators activate G proteins that upregulate cyclic adenosine monophosphate (cAMP) generation, which in turn activates the protein kinase A pathway for VEGF production, whereas KOR activation suppresses VEGF production by promoting Gαi/o inhibition of adenylyl cyclase, which decreases cAMP levels and attenuates protein kinase A activation29,30 It has been reported that the downregulation of KOR expression in hepatocellular carcinoma had a strong association with poor prognosis31. The gene discussed is VEGFA; the disease is hepatocellular carcinoma.