Overexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repair
Abstract Glioblastoma (GBM) is the most common malignant primary brain cancer with poor prognosis due to the resistant to current treatments, including the first-line drug temozolomide (TMZ). Accordingly, it is urgent to clarify the mechanism of chemotherapeutic resistance to improve the survival ra...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-01-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07363-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832585382675349504 |
|---|---|
| author | Yuchen Wei Peng Wang Jianhui Zhao Xin Fan Jun Jiang Xiuli Mu Yuzhou Wang Angang Yang Rui Zhang Shijie Hu Zhangyan Guo |
| author_facet | Yuchen Wei Peng Wang Jianhui Zhao Xin Fan Jun Jiang Xiuli Mu Yuzhou Wang Angang Yang Rui Zhang Shijie Hu Zhangyan Guo |
| author_sort | Yuchen Wei |
| collection | DOAJ |
| description | Abstract Glioblastoma (GBM) is the most common malignant primary brain cancer with poor prognosis due to the resistant to current treatments, including the first-line drug temozolomide (TMZ). Accordingly, it is urgent to clarify the mechanism of chemotherapeutic resistance to improve the survival rate of patients. In the present study, by integrating comprehensive non-coding RNA-seq data from multiple cohorts of GBM patients, we identified that a series of miRNAs are frequently downregulated in GBM patients compared with the control samples. Among them, a high level of miR-124 is closely associated with a favorable survival rate in the clinical patients. In the phenotype experiment, we demonstrated that miR-124 overexpression increases responsiveness of GBM cells to TMZ-induced cell death, and vice versa. In the mechanistic study, we for the first time identified that RAD51, a key functional molecule in DNA damage repair, is a novel and bona fide target of miR-124 in GBM cells. Given that other miR-124-regulated mechanisms on TMZ sensitivity have been reported, we performed recue experiment to demonstrate that RAD51 is essential for miR-124-mediated sensitivity to TMZ in GBM cells. More importantly, our in vivo functional experiment showed that combinational utilization of miR-124 overexpression and TMZ presents a synergetic therapeutic benefit in the orthotopic GBM mice model. Taken together, we rationally explained a novel and important mechanism of the miR-124-mediated high sensitivity to TMZ-induced cell death in GBM and provided evidence to support that miR-124-RAD51 regulatory axis could be a promising candidate in the comprehensive treatment with TMZ in GBM. |
| format | Article |
| id | doaj-art-c09dd3d220644bfb993d6f3ed94d4a08 |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-c09dd3d220644bfb993d6f3ed94d4a082025-01-26T12:54:44ZengNature Publishing GroupCell Death and Disease2041-48892025-01-0116111510.1038/s41419-025-07363-zOverexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repairYuchen Wei0Peng Wang1Jianhui Zhao2Xin Fan3Jun Jiang4Xiuli Mu5Yuzhou Wang6Angang Yang7Rui Zhang8Shijie Hu9Zhangyan Guo10State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityDepartment of Neurosurgery, The First Medical Center of Chinese PLA General HospitalDepartment of Critical Care Medicine, Hainan Hospital of Chinese PLA General HospitalDepartment of Otolaryngology Head and Neck Surgery, Tangdu Hospital, Fourth Military Medical UniversityDepartment of Health Service, Base of Health Service, Fourth Military Medical UniversityState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Immunology, Fourth Military Medical UniversityState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Immunology, Fourth Military Medical UniversityState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Immunology, Fourth Military Medical UniversityState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical UniversityDepartment of Neurosurgery, Xijing Hospital, Fourth Military Medical UniversityState Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Immunology, Fourth Military Medical UniversityAbstract Glioblastoma (GBM) is the most common malignant primary brain cancer with poor prognosis due to the resistant to current treatments, including the first-line drug temozolomide (TMZ). Accordingly, it is urgent to clarify the mechanism of chemotherapeutic resistance to improve the survival rate of patients. In the present study, by integrating comprehensive non-coding RNA-seq data from multiple cohorts of GBM patients, we identified that a series of miRNAs are frequently downregulated in GBM patients compared with the control samples. Among them, a high level of miR-124 is closely associated with a favorable survival rate in the clinical patients. In the phenotype experiment, we demonstrated that miR-124 overexpression increases responsiveness of GBM cells to TMZ-induced cell death, and vice versa. In the mechanistic study, we for the first time identified that RAD51, a key functional molecule in DNA damage repair, is a novel and bona fide target of miR-124 in GBM cells. Given that other miR-124-regulated mechanisms on TMZ sensitivity have been reported, we performed recue experiment to demonstrate that RAD51 is essential for miR-124-mediated sensitivity to TMZ in GBM cells. More importantly, our in vivo functional experiment showed that combinational utilization of miR-124 overexpression and TMZ presents a synergetic therapeutic benefit in the orthotopic GBM mice model. Taken together, we rationally explained a novel and important mechanism of the miR-124-mediated high sensitivity to TMZ-induced cell death in GBM and provided evidence to support that miR-124-RAD51 regulatory axis could be a promising candidate in the comprehensive treatment with TMZ in GBM.https://doi.org/10.1038/s41419-025-07363-z |
| spellingShingle | Yuchen Wei Peng Wang Jianhui Zhao Xin Fan Jun Jiang Xiuli Mu Yuzhou Wang Angang Yang Rui Zhang Shijie Hu Zhangyan Guo Overexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repair Cell Death and Disease |
| title | Overexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repair |
| title_full | Overexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repair |
| title_fullStr | Overexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repair |
| title_full_unstemmed | Overexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repair |
| title_short | Overexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repair |
| title_sort | overexpression of mir 124 enhances the therapeutic benefit of tmz treatment in the orthotopic gbm mice model by inhibition of dna damage repair |
| url | https://doi.org/10.1038/s41419-025-07363-z |
| work_keys_str_mv | AT yuchenwei overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT pengwang overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT jianhuizhao overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT xinfan overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT junjiang overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT xiulimu overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT yuzhouwang overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT angangyang overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT ruizhang overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT shijiehu overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair AT zhangyanguo overexpressionofmir124enhancesthetherapeuticbenefitoftmztreatmentintheorthotopicgbmmicemodelbyinhibitionofdnadamagerepair |