SFRP2 Drives Aerobic Glycolysis and Tumor Progression in Ovarian Cancer via Transcriptional Upregulation of PTK2B

Background Ovarian cancer is a highly lethal gynecologic malignancy, with metabolic reprogramming being a key contributor to its progression and therapy resistance. Although Secreted Frizzled-Related Protein 2 (SFRP2) is implicated in cancer, its functional role and molecular mechanisms in ovarian cancer, particularly in regulating metabolic pathways, remain poorly defined. Methods Bioinformatics analysis of GEO (GSE66957) and TCGA-OV datasets was performed to assess SFRP2 expression and its correlation with prognosis. Immunohistochemistry (IHC) on a human ovarian cancer tissue microarray was used for clinical validation. SFRP2 was knocked down or overexpressed in ovarian cancer cell lines (HEY, SK-OV-3) using lentiviral shRNAs. Functional assays (CCK-8, colony formation, apoptosis, migration) and metabolic assays (glucose consumption, lactate/ATP production, ECAR/OCR) were conducted. The mechanistic link between SFRP2, transcription factor CEBPA, and downstream target PTK2B was investigated using co-immunoprecipitation (Co-IP), nuclear-cytoplasmic fractionation, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. Rescue experiments were performed both in vitro and in vivo (xenograft mouse models). Results SFRP2 was significantly overexpressed in ovarian cancer tissues and cell lines, and high SFRP2 expression correlated with advanced disease and poor patient survival. SFRP2 knockdown suppressed cell proliferation, colony formation, and migration, while promoting apoptosis. Gene set enrichment analysis linked SFRP2 to the CCR5 signaling pathway, prompting an investigation into glycolysis. SFRP2 depletion impaired aerobic glycolysis, reducing glucose uptake, lactate/ATP production, and ECAR, while increased OCR. Conversely, SFRP2 overexpression enhanced glycolytic flux and tumorigenic phenotypes, which were abrogated by the glycolytic inhibitor 2-DG. Mechanistically, SFRP2 interacted with the transcription factor CEBPA, promoted its nuclear translocation, and enhanced its binding to the PTK2B promoter, leading to PTK2B transcriptional activation. Crucially, PTK2B knockdown reversed the pro-glycolytic and pro-tumorigenic effects of SFRP2 overexpression both in vitro and in vivo. Conclusion Our findings identify a novel SFRP2/CEBPA/PTK2B signaling axis that drives aerobic glycolysis and malignant progression in ovarian cancer, highlighting SFRP2 and PTK2B as potential prognostic markers and therapeutic targets.