Guanylate-binding protein 2 (GBP2) drives pancreatic cancer cell proliferation by promoting cell cycle progression via the SP1/SKP2/P27 axis

Guanylate-binding protein 2 (GBP2) has been reported to be involved in the progression of various human malignancies, but its specific functions and underlying molecular mechanisms in pancreatic cancer remain poorly understood. The expression level of GBP2 in pancreatic cancer tissues and cell lines was detected, and the correlation between GBP2 expression and clinicopathological features as well as patient prognosis was analyzed. In vitro and in vivo experiments were performed to investigate the effect of GBP2 on pancreatic cancer cell proliferation and cell cycle progression. RNA-sequencing was conducted to screen downstream regulatory targets of GBP2, and molecular mechanism assays (including ubiquitination assay, co-immunoprecipitation) were carried out to verify the regulatory relationship between GBP2, SP1, TRIM25 and SKP2. GBP2 was significantly upregulated in pancreatic cancer tissues and cell lines, and high GBP2 expression was closely associated with a poor prognosis, an advanced TNM stage and a higher tumor grade. Functional experiments showed that GBP2 promotes pancreatic cancer cell proliferation by inducing cell cycle progression. Mechanistically, GBP2 competes with the E3 ubiquitin ligase TRIM25 for binding to transcription factor SP1, thereby inhibiting SP1 ubiquitination and proteasomal degradation. The stabilized SP1 further enhances its binding to the SKP2 promoter, upregulates SKP2 transcription, and activates the SKP2/p27 signaling axis to drive tumor progression. This study reveals a novel GBP2–SP1–SKP2–p27 signaling pathway that promotes pancreatic cancer progression. GBP2 may serve as a potential therapeutic target for pancreatic cancer, which requires further validation through pharmacological studies and patient-derived organoid models.