High-Glucose Environment Promotes Radioresistance in Colorectal Cancer via SERPINE1-Enhanced DNA Repair and Anti-Apoptosis.

BACKGROUND

Patients with colorectal cancer (CRC) and comorbid hyperglycemia often exhibit poor responses to preoperative concurrent chemoradiotherapy (CCRT), leading to unfavorable clinical outcomes. However, how hyperglycemia contributes to CRC radioresistance remains incompletely understood. This study aimed to elucidate the molecular mechanisms by which high-glucose exposure promotes radioresistance in CRC.

METHODS

CRC cell lines (SW480 and HCT116) were cultured under normal-glucose (5 mM), high-glucose (25 mM), or mannitol osmotic control conditions to assess malignant behaviors and radiosensitivity. Relative miRNA expression changes from pooled plasma exosomal miRNA profiling were integrated with TargetScan, miRDB, GeneCards, and TCGA analyses to screen for candidate mediators. Candidate SERPINE1-regulating miRNAs were validated using mimic/inhibitor assays. The functional role of SERPINE1 was validated using siRNA knockdown and plasmid overexpression assays, followed by assays of clonogenic survival, apoptosis, γ-H2AX foci kinetics, and DNA repair-associated protein expression.

RESULTS

High-glucose culture significantly enhanced CRC cell proliferation, migration, invasion, epithelial-mesenchymal transition, cancer stemness, and clonogenic radioresistance, whereas mannitol did not reproduce these effects. Integrated exploratory exosomal miRNA and bioinformatic analyses identified SERPINE1 as a candidate mediator associated with hyperglycemia, radioresistance, and poor prognosis. Selected hyperglycemia-associated miRNAs functionally modulated SERPINE1 protein expression in CRC cells. We confirmed that high glucose upregulates SERPINE1 expression in vitro. Mechanistically, SERPINE1 knockdown suppressed malignant phenotypes, reduced stemness-associated traits, enhanced irradiation-induced apoptosis, increased residual γ-H2AX foci, and attenuated DNA repair-associated protein responses. Conversely, SERPINE1 overexpression promoted aggressive phenotypes, reduced apoptotic signaling, accelerated γ-H2AX foci resolution, and enhanced radioresistance.

CONCLUSION

High-glucose exposure promotes CRC malignancy and radioresistance, at least in part, through SERPINE1 upregulation. SERPINE1 contributes to radioresistance by attenuating apoptosis and facilitating radiation-induced DNA damage resolution. These findings support SERPINE1 as a key mechanistic mediator linking high-glucose exposure to radioresistance in CRC cell models. Because the exosomal miRNA profiling was performed using pooled plasma samples, the resulting miRNA findings should be regarded as exploratory and do not constitute a validated biomarker signature. The potential clinical relevance of SERPINE1 requires further validation in independent patient cohorts and physiologically relevant in vivo models.