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.
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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)
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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
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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
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