Polymorphism in the Hsa-miR-4274 seed region influences the expression of PEX5 and enhances radiotherapy resistance in colorectal cancer

Abstract

Identifying biomarkers for predicting radiotherapy efficacy is crucial for optimizing personalized treatments. We previously reported that rs1553867776 in the miR-4274 seed region can predict survival in patients with rectal cancer receiving postoperative chemoradiation therapy. Hence, to investigate the molecular mechanism of the genetic variation and its impact on the radiosensitivity of colorectal cancer (CRC), in this study, bioinformatics analysis is combined with functional experiments to confirm peroxisomal biogenesis factor 5 (PEX5) as a direct target of miR-4274. The miR-4274 rs1553867776 variant influences the binding of miR-4274 and PEX5 mRNA, which subsequently regulates PEX5 protein expression. The interaction between PEX5 and Ku70 was verified by co-immunoprecipitation and immunofluorescence. A xenograft tumor model was established to validate the effects of miR-4274 and PEX5 on CRC progression and radiosensitivity in vivo. The overexpression of PEX5 enhances radiosensitivity by preventing Ku70 from entering the nucleus and reducing the repair of ionizing radiation (IR)-induced DNA damage by the Ku70/Ku80 complex in the nucleus. In addition, the enhanced expression of PEX5 is associated with increased IR-induced ferroptosis. Thus, targeting this mechanism might effectively increase the radiosensitivity of CRC. These findings offer novel insights into the mechanism of cancer radioresistance and have important implications for clinical radiotherapy.

Keywords

colorectal cancer / polymorphism / miR-4274 / PEX5 / radiotherapy resistance

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Acknowledgments

This work is supported by grants from the National Natural Science Foundation (Grant No. 81972859 to W.T.), CAMS Innovation Fund for Medical Sciences (CIFMS) (Grant No. 2021-I2M-1-013 to D.L. and W.T.), and State Key Laboratory of Molecular Oncology Grants (Grant No. SKLMO-2021-03 to W.T. and SKLMO-KF-2023-03 to D.L.)

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1082-6 and is accessible for authorized users.

Compliance with ethics guidelines

Conflicts of interest Qixuan Lu, Ningxin Ren, Hongxia Chen, Shaosen Zhang, Ruoqing Yan, Mengjie Li, Linlin Zheng, Wen Tan, and Dongxin Lin declare that they have no conflict of interest.

The study was approved by the appropriate institutional and/or national research ethics committee and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study. All institutional and national guidelines for the care and use of laboratory animals were followed.

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