AURKA promotes angiogenesis in uveal melanoma via activation of the JAK2/STAT3/VEGFA signaling pathway.

PURPOSE

Uveal melanoma (UM) is a highly aggressive malignancy with a poor prognosis, where angiogenesis plays a pivotal role in tumor metastasis. Aurora kinase A (AURKA) is widely recognized for its role in regulating cell cycle progression and promoting tumorigenesis; however, its involvement in UM-associated angiogenesis remains largely unexplored. Artesunate (ART), a bioactive compound derived from traditional Chinese medicine, has recently garnered attention for its promising anti-cancer properties. This study aimed to elucidate the role of AURKA in UM angiogenesis and assess the potential of ART as an effective AURKA inhibitor.

METHODS

The TCGA database was utilized to investigate AURKA expression and its prognostic significance in UM. Kaplan-Meier survival analysis, Cox regression and nomogram modeling were applied to assess its prognostic value. The impact of AURKA on angiogenesis in UM was assessed through HUVECs tube formation, migration and CAM assays in vitro. WB experiments were performed to explore the mechanisms by which AURKA regulated angiogenesis. Molecular docking and molecular dynamic simulations were used to investigate the binding sites and binding affinity of ART on AURKA. Finally, experiments in vivo using a nude mouse xenograft model were performed to confirm the effects of ART and knocking down AURKA on tumor growth and angiogenesis.

RESULTS

High AURKA expression was associated with poor clinical prognosis in UM patients. AURKA promoted angiogenesis via activation of the JAK2/STAT3/VEGFA pathway. ART formed stable hydrogen bonds with AURKA and inhibited its pro-angiogenic effects. In experiments in vivo, ART combined with knocking down AURKA significantly suppressed tumor proliferation and decreased the levels of the angiogenesis marker CD31 and the proliferation marker Ki67.

CONCLUSIONS

AURKA promoted UM progression by driving angiogenesis through the JAK2/STAT3/VEGFA signaling pathway. ART effectively inhibited the function of AURKA, offering a promising therapeutic strategy for UM. The synergistic effects of ART and knocking down AURKA further highlighted its potential as a novel anti-angiogenic therapy for UM.