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

Abstract

BACKGROUND:

Although programmed cell death-ligand 1 (PD-L1) plays a well-known 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 PD-L1-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.

• Authors: Yufei Yang, Lingfang Xia, Yong Wu, Hongyu Zhou, Xin Chen, Haoran Li, Midie Xu, Zihao Qi, Ziliang Wang, Huizhen Sun, Xi Cheng
• Journal: Cancer communications (London, England) (Cancer Commun (Lond)) Vol. 41 Issue 6 Pg. 511-527 (06 2021) ISSN: 2523-3548 [Electronic] United States
• PMID: 33939321 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.

Chemical References

• B7-H1 Antigen
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Animals
• B7-H1 Antigen (genetics)
• Female
• Humans
• Mice
• Ovarian Neoplasms (drug therapy, genetics)
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-2 (genetics)
• Zebrafish