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

Yufei Yang; Lingfang Xia; Yong Wu; Hongyu Zhou; Xin Chen; Haoran Li; Midie Xu; Zihao Qi; Ziliang Wang; Huizhen Sun; Xi Cheng

doi:10.1002/cac2.12157

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

Cancer Commun (Lond). 2021 Jun;41(6):511-527. doi: 10.1002/cac2.12157. Epub 2021 May 3.

Authors

Yufei Yang^{1

2}, Lingfang Xia^{1

2}, Yong Wu¹, Hongyu Zhou^{1

2}, Xin Chen³, Haoran Li^{1

2}, Midie Xu^{4

2}, Zihao Qi⁵, Ziliang Wang^{1

3

6}, Huizhen Sun³, Xi Cheng^{1

2}

Affiliations

¹ Department of Gynecological Oncology and Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, P. R. China.
³ Department of Gynecology and Obstetrics, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200092, P. R. China.
⁴ Department of Pathology and Tissue Bank, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.
⁵ Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, P. R. China.
⁶ Clinical Research Unit of Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine Shanghai 200071, P. R. China.

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.

Keywords: Angiogenesis; Apatinib; Metastasis; Ovarian Cancer; PD-L1; VEGFR2; Zebrafish; c-JUN.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B7-H1 Antigen* / genetics
Female
Humans
Mice
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / genetics
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-2 / genetics
Zebrafish

Substances

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