Investigating the Functional Role of LncRNA UCA1 in Mediating Aerobic Glycolysis in High-grade Serous Ovarian Carcinoma

Abstract

Long non-coding RNAs (lncRNAs) are important regulators in cancer biology, with growing evidence implicating them in metabolic reprogramming. However, the role of the lncRNA Urothelial Cancer-Associated 1 (UCA1) in modulating aerobic glycolysis, commonly known as the Warburg effect and one of the most well-established metabolic features of cancer cells, in high-grade serous ovarian carcinoma (HGSC), the most common and clinically aggressive subtype, remains poorly understood. Although previous studies have reported oncogenic functions of UCA1 in ovarian cancer, these investigations were largely conducted in non-serous cell lines. In this study, we employed HGSC-relevant cell models to investigate the specific function of UCA1 in regulating aerobic glycolysis. Gain-of-function models were established by overexpressing UCA1 in fallopian tube secretory epithelial cells (FTSECs), the cellular origin of HGSC, while loss-of-function models were generated by siRNA-mediated knockdown of UCA1 in two HGSC cell lines, CaOV3 and UWB1.289. Functional assays revealed that UCA1 overexpression significantly increased glucose uptake and lactate production, whereas UCA1 knockdown reduced these glycolytic parameters. Real-time metabolic flux analysis using the Agilent Seahorse XFe96 Analyzer demonstrated that UCA1 expression remodels cellular energy metabolism, as evidenced by suppressed oxygen consumption rate (OCR) and elevated glycolytic proton efflux rate (glycoPER), hallmarks of a metabolic shift toward aerobic glycolysis. Transcriptomic analysis via RNA-seq and small RNA-seq revealed that UCA1 modulation did not significantly alter the mRNA expression of key glycolytic enzymes (HK2, PFKM, PKM2) or glucose transporters (GLUT1), and no overlapping differentially expressed miRNAs were identified across cell models, suggesting that UCA1 promotes aerobic glycolysis through non-transcriptional mechanisms. Collectively, our findings establish UCA1 as a novel metabolic regulator in HGSC, promoting aerobic glycolysis through mechanisms independent of glycolytic gene transcription. These results not only uncover a critical metabolic pathway that may contribute to HGSC pathogenesis but also highlight the UCA1-glycolysis axis as a potential avenue for future therapeutic exploration.