Novel Extracellular Exosome Promoting Tumor Aggressiveness and Metastasis in Gynecologic Cancer

Cancer-derived extracellular exosomes (EXs) promote tumor metastasis. This study investigates novel EXs influencing tumor aggressiveness and metastasis in gynecologic cancer. Data from ES2-derived EXs on aggressive ES2 cells and ascites-derived mesenchymal-type ovarian carcinoma stromal progenitor cells (MSC-OCSPCs) were analyzed using LC-MS/MS and integrated with TCGA survival analysis. Two novel EXs, UBE2NL and HIST2H3PS2, were identified in more aggressive ES2-derivatives and MSC-OCSPCs cells, but not in less aggressive SKOV3 cells. High UBE2NL and HIST2H3PS2 expression in EOC tissues was associated with advanced-stage carcinoma (p<0.01) and shorter overall survival (p<0.01). Besides, high HIST2H3PS2 expression in endometrial cancer (EC) tissues was also associated with shorter overall survival (p<0.001) in all stages and advanced stages (p<0.0001). In vitro, SKOV3 cells overexpressing UBE2NL or HIST2H3PS2 exhibited significantly greater invasion ability than controls (p<0.001), further enhanced by their respective EXs (p<0.001). In contrast, ES2 knockdown UBE2NL reduced invasion ability than ES2 cells (p<0.001). In vivo, mice injected with ES2/shUBE2NL cells had a higher survival rate (p<0.001) and fewer disseminated tumors (p<0.05); in contrast, those injected with SKOV3/HIST2H3PS2 cells showed greater tumor dissemination (p<0.01) and more severe ascites (p<0.05) than controls. Tumor dissemination increased in mice receiving SKOV3/HIST2H3PS2 cells with EXs than those controls (p<0.05). These findings suggest that UBE2NL and HIST2H3PS2 expression and EXs contribute to tumor aggressiveness and metastasis in gynecologic cancer.