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Background <p>Ovarian cancer is a highly lethal gynecologic malignancy, with metabolic reprogramming being a key contributor to its progression and therapeutic resistance. Although Secreted Frizzled-Related Protein 2 (SFRP2) has been implicated in various cancers, its functional role and molecular mechanisms in ovarian cancer, particularly in regulating metabolic pathways, remain poorly defined.</p> Methods <p>Bioinformatic analyses of GEO (GSE66957) and TCGA-OV datasets were performed to assess SFRP2 expression and its prognostic correlation. 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 and SK-OV-3) using lentiviral shRNA vectors. 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).</p> Results <p>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. Mechanistically, SFRP2 interacted with the transcription factor CEBPA, promoted its nuclear translocation, and enhanced its occupancy at the PTK2B promoter, thereby driving PTK2B transcriptional activation. This SFRP2/CEBPA/PTK2B axis further activates the AKT/mTOR signaling pathway, upregulating key glycolytic enzymes. Importantly, inhibiting glycolysis with 2-DG or knocking down PTK2B effectively reversed the oncogenic effects of SFRP2 both in vitro and in vivo.</p> Conclusion <p>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.</p>

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SFRP2 drives aerobic glycolysis and tumor progression in ovarian cancer by transcriptional upregulation of PTK2B

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Jindong Sheng,
  • Yiwen Xing,
  • Jing Luan,
  • Xiangyu Liu,
  • Hualin Song,
  • Lu Sun,
  • Min Yu,
  • Xin Fu,
  • Huijuan Wu,
  • Ying Chen,
  • Wenxin Liu,
  • Ke Wang

摘要

Background

Ovarian cancer is a highly lethal gynecologic malignancy, with metabolic reprogramming being a key contributor to its progression and therapeutic resistance. Although Secreted Frizzled-Related Protein 2 (SFRP2) has been implicated in various cancers, its functional role and molecular mechanisms in ovarian cancer, particularly in regulating metabolic pathways, remain poorly defined.

Methods

Bioinformatic analyses of GEO (GSE66957) and TCGA-OV datasets were performed to assess SFRP2 expression and its prognostic correlation. 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 and SK-OV-3) using lentiviral shRNA vectors. 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. Mechanistically, SFRP2 interacted with the transcription factor CEBPA, promoted its nuclear translocation, and enhanced its occupancy at the PTK2B promoter, thereby driving PTK2B transcriptional activation. This SFRP2/CEBPA/PTK2B axis further activates the AKT/mTOR signaling pathway, upregulating key glycolytic enzymes. Importantly, inhibiting glycolysis with 2-DG or knocking down PTK2B effectively reversed the oncogenic effects of SFRP2 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.