High-Glucose Environment Promotes Radioresistance in Colorectal Cancer via SERPINE1-Enhanced DNA Repair and Anti-Apoptosis.
7 affiliations
- 1Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 2Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- 3Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 4Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 5Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 6Department of Radiation Oncology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- 7Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
Abstract
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.
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BibTeX
@article{ke2026highglucose,
title = {{High-Glucose Environment Promotes Radioresistance in Colorectal Cancer via SERPINE1-Enhanced DNA Repair and Anti-Apoptosis.}},
author = {Chien-Chih Ke and Yu-Chen Zhang and Po-Jen Wang and Chen-Yu Wang and Shih-Hsun Kuo and Chia-Yang Li and Ming-Yii Huang and Ya-Ju Hsieh},
journal = {International journal of medical sciences},
year = {2026},
month = sep,
doi = {10.7150/ijms.130794},
url = {https://europepmc.org/article/MED/42910127},
note = {CC BY},
}
RIS
TY - JOUR
TI - High-Glucose Environment Promotes Radioresistance in Colorectal Cancer via SERPINE1-Enhanced DNA Repair and Anti-Apoptosis.
AU - Chien-Chih Ke
AU - Yu-Chen Zhang
AU - Po-Jen Wang
AU - Chen-Yu Wang
AU - Shih-Hsun Kuo
AU - Chia-Yang Li
AU - Ming-Yii Huang
AU - Ya-Ju Hsieh
PY - 2026
DA - 2026/09/18
JO - International journal of medical sciences
DO - 10.7150/ijms.130794
UR - https://europepmc.org/article/MED/42910127
AB - 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.
SN - 1449-1907
ER -