Chia-Hao Liu

Programmed death-ligand 1 upregulation is associated with poor prognosis in patients with epithelial ovarian cancer

Background: The clinical significance of programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC), particularly its association with platinum resistance (PR) and prognosis, remains unclear. This study aimed to evaluate the relationship between PD-L1 expression and PR in EOC and investigate cisplatin-induced PD-L1 modulation using in vitro and in vivo models. Methods: We retrospectively analyzed 189 patients with EOC, treated between 2014 and 2020. Tumor PD-L1 expression was assessed by immunohistochemistry (IHC) using the combined positive score (CPS). Serum PD-L1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Cisplatin-induced PD-L1 regulation was examined in paired platinum-sensitive (PS: A2780 and ES2) and PR (A2780R and ES2R) cell lines and xenograft models. Results: High tumor PD-L1 expression (CPS ≥10) was more frequent in PR (38.5%) than in PS patients (19.0%, p < 0.01), and was associated with higher recurrence rates ( p < 0.001) and shorter overall survival ( p < 0.001). Serum PD-L1 concentrations were significantly elevated in patients with endometrioid and clear cell histologies compared with those in the control group ( p < 0.05). In vitro, PD-L1 expression was upregulated in PR cell lines compared with parental PS cell lines and was further increased following cisplatin exposure in a dose- and time-dependent manner. Xenograft models confirmed that cisplatin induces PD-L1 upregulation in both tumor tissue and serum, with more pronounced effects observed in PR tumors. Conclusion: PD-L1 upregulation (CPS ≥10) is associated with PR, disease recurrence, and poor prognosis in EOC. Endometrioid and clear cell histologic subtypes demonstrated higher baseline PD-L1 expression in our cohort. Cisplatin-induced PD-L1 upregulation represents a tumor-intrinsic response, particularly in PR tumor cells, highlighting PD-L1 as a histology-specific marker of poor prognosis and a potential therapeutic target in platinum-resistant EOC.

Targeting the ST3 beta‐galactoside alpha‐2,3‐sialyltransferase 1 ( ST3Gal1 ) as a potential therapeutic strategy to overcome anti‐ VEGF resistance in endometrial cancer

Abstract Objective To investigate the role of ST3 beta‐galactoside alpha‐2,3‐sialyltransferase 1 (ST3Gal1) in endometrial cancer (EC) progression and its potential as a therapeutic target to enhance the efficacy of antiangiogenic treatment. Methods ST3Gal1 expression and its clinical relevance were analyzed in EC tissues. Functional assays evaluated its effects on vascular endothelial growth factor‐A (VEGF‐A) expression, epithelial–mesenchymal transition (EMT), and cell invasiveness. Mechanistic studies, including Duolink proximity ligation assays and co‐immunoprecipitation, examined ST3Gal1–VEGF‐A interactions. ST3Gal1 was inhibited genetically or pharmacologically using soyasaponin I (SsaI), both in vitro and in xenograft models, alone or combined with bevacizumab. Angiogenic and EMT marker expression and focal adhesion kinase (FAK)/paxillin pathway activation were assessed. Results ST3Gal1 was amplified and overexpressed in EC and correlated with advanced stage, deep myometrial invasion, and poor prognosis. It directly glycosylated VEGF‐A and activated FAK/paxillin signaling, promoting VEGF‐A expression and EMT. ST3Gal1 inhibition via SsaI reduced VEGF‐A signaling, reversed EMT marker expression, and suppressed cell migration and invasion, particularly in RL95‐2 cells. In vivo, SsaI significantly inhibited tumor growth and angiogenesis, with the most pronounced effect observed in combination with bevacizumab. Dual treatment disrupted ST3Gal1–VEGF‐A interactions and downregulated angiogenic and EMT markers. Conclusion ST3Gal1 promotes EC progression by enhancing VEGF‐A signaling and EMT via the FAK/paxillin pathway. Its inhibition improves the efficacy of antiangiogenic therapy, supporting ST3Gal1 as a promising therapeutic target to overcome anti‐VEGF‐A resistance in advanced EC.