Proteomics analysis of serum extracellular vesicle identifies UCHL1 as a potential therapeutic target for high grade serous ovarian cancer
Menée à partir de lignées cellulaires, d'explants dérivés de patientes atteintes d'un cancer séreux ovarien de haut grade, d'une analyse immunohistochimique d'échantillons tissulaires et d'une analyse protéomique de vésicules extracellulaires (VE), cette étude identifie 28 protéines de VE surexprimées dans les tumeurs et démontre que l'inhibition de la protéine UCHL1 bloque le processus invasif des cellules cancéreuses et favorise leur apoptose
Background : This study characterised the proteins from EVs in the serum from high-grade serous ovarian cancer (HGSOC) compared to healthy controls.
Methods : Serum EVs were isolated, followed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify differentially expressed proteins. We validated the expression of 4 EV proteins increased in cancer serum (KRT4, MARCKS, SPP1/OPN, and UCHL1) in HGSOC tissues and normal ovarian tissues using online databases and independent HGSOC patient tissue cohorts. We additionally investigated the effects of the UCHL1 inhibitor, LDN-57444, on HGSOC cell metabolic activity, motility, invasion, and apoptosis in HGSOC tissues using patient-derived explant assays.
Results : Proteomics analysis identified 28 EV proteins that were upregulated in HGSOC compared to healthy controls. We confirmed that UCHL1 protein levels were increased in HGSOC tissues compared to normal (OSE and FT) and benign epithelium. High stromal UCHL1 levels were associated with reduced progression-free survival in HGSOC. The UCHL1 inhibitor, LDN-57444, reduced the cell metabolic activity of ovarian cancer cell lines and primary ovarian cancer cells with high UCHL1 levels. LDN-57444 blocked the motility and invasion of OVCAR3 cells and promoted apoptosis in the HGSOC patient explant tissue assay.
Conclusion : UCHL1 has the potential to be used as a novel prognostic and therapeutic target for HGSOC.
British Journal of Cancer , résumé, 2025