Programmed death ligand-1 regulates angiogenesis and metastasis by participating in the c-JUN/VEGFR2 signaling axis in ovarian cancer

Background:Although programmed cell death-ligand 1(PD-L1)plays a wellknown function in immune checkpoint response by interacting with programmed cell death-1(PD-1),the cell-intrinsic role of PD-L1 in tumors is still unclear.Here,we explored the molecular regulatory mechanism of PD-L1 in the progression and metastasis of ovarian cancer.Methods:Immunohistochemistry of benign tissues and ovarian cancer samples was performed,followed by migration,invasion,and angiogenesis assays in PDL1-knockdown ovarian cancer cells.Immunoprecipitation,mass spectrometry,and chromatin immunoprecipitation were conducted along with zebrafish and mouse experiments to explore the specific functions and mechanisms of PD-L1 in ovarian cancer.Results:Our results showed that PD-L1 induced angiogenesis,which further promoted cell migration and invasion in vitro and in vivo of ovarian cancer.Mechanistically,PD-L1 was identified to directly interact with vascular endothelial growth factor receptor-2(VEGFR2)and then activated the FAK/AKT pathway,which further induced angiogenesis and tumor progression,leading to poor prognosis of ovarian cancer patients.Meanwhile,PD-L1 was found to be regulated by the oncogenic transcription factor c-JUN at the transcriptional level,which enhanced the expression of PD-L1 in ovarian cancer.Furthermore,we demonstrated that PD-L1 inhibitor durvalumab,combined with the antiangiogenic drug,apatinib,could enhance the effect of anti-angiogenesis and the inhibition of cell migration and invasion.Conclusion:Our results demonstrated that PD-L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c-JUN/VEGFR2 signaling axis,suggesting that the combination of PD-L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients.