Hypoxia-induced circ_0017521 enhances glycolysis and promotes NSCLC progression via upregulating the PFKFB3/PI3K-AKT pathway.

Abstract

The hypoxic microenvironment is a critical feature of malignant progression in non-small cell lung cancer (NSCLC). However, the regulatory role of circular RNAs (circRNAs) in this context remains incompletely understood. Hypoxia-related circRNAs were screened by integrating GEO datasets, and the expression of circ_0017521 in hypoxia-treated cells was validated using qRT-PCR. RNase R digestion and actinomycin D assays were employed to assess its stability. Biological functions were evaluated through CCK-8, colony formation, Transwell, flow cytometry, and glycolytic metabolism assays. Dual-luciferase reporter, RNA pull-down, and rescue experiments were conducted to elucidate the circ_0017521/miR-532-3p/PFKFB3 axis. A nude mouse xenograft model was constructed. circ_0017521 was specifically upregulated in NSCLC tissues and hypoxia-treated cells, exhibiting remarkable stability compared to linear AKR1E2 and primarily localizing in the cytoplasm. Under hypoxic conditions, knockdown of circ_0017521 noticeably inhibited NSCLC cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and glycolysis, while promoting apoptosis. Mechanistically, circ_0017521 competitively bound to miR-532-3p, relieving its suppression of PFKFB3 and thereby activating the PI3K/AKT signaling pathway. Upregulation of PFKFB3 drove the expression of glycolytic enzymes (GLUT1, LDHA, HK2) and synergistically activated EMT. Animal experiments confirmed that silencing circ_0017521 suppressed tumor growth and glycolysis. This study revealed that hypoxia-induced circ_0017521 activated the PI3K/AKT pathway through the miR-532-3p/PFKFB3 axis, synergistically driving EMT and glycolysis, thereby promoting NSCLC progression.