MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling
Abstract Background Due to the poor prognosis of patients suffering malignant brain tumors such as glioblastoma multiforme (GBM), the search for new therapeutic strategies with more efficacy and higher survival rate is of utmost urgency. Growing evidence suggests that alterations in autophagy and me...
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BMC
2025-08-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03504-6 |
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| author | Marta Torrecilla-Parra Virginia Pardo-Marqués Antonio C. Fuentes-Fayos Miguel E. G-García Mario Fernández-de Frutos José L. López-Aceituno Cristina Puigdueta Carmen Zamora Ana Pérez-García Juan F. Aranda Rebeca Busto Manuel D. Gahete Raúl M. Luque Cristina M. Ramírez |
| author_facet | Marta Torrecilla-Parra Virginia Pardo-Marqués Antonio C. Fuentes-Fayos Miguel E. G-García Mario Fernández-de Frutos José L. López-Aceituno Cristina Puigdueta Carmen Zamora Ana Pérez-García Juan F. Aranda Rebeca Busto Manuel D. Gahete Raúl M. Luque Cristina M. Ramírez |
| author_sort | Marta Torrecilla-Parra |
| collection | DOAJ |
| description | Abstract Background Due to the poor prognosis of patients suffering malignant brain tumors such as glioblastoma multiforme (GBM), the search for new therapeutic strategies with more efficacy and higher survival rate is of utmost urgency. Growing evidence suggests that alterations in autophagy and metabolism critically contribute to the pathogenesis and progression of GBM. In this context, microRNAs are known to regulate autophagy and associated cellular functions, which point them as promising therapeutic candidates. We previously established the role of miR-7 in regulating relevant metabolic pathways related to insulin signaling and cholesterol homeostasis. Methods Bioinformatics analysis was performed to identify miR-7 target genes potentially involved in the regulation of metabolism and cellular processes related to GBM. Ectopic expression of miR-7 was assessed to investigate its role in macroautophagy and energy metabolism. In vivo, miR-7 levels were restored in a mouse GBM xenograft model to evaluate its potential therapeutic effect in already established tumors. Additional mechanistic approaches, including transcriptomics, bioinformatics, and histopathological analyses, indicate that miR-7 modifies the tumor phenotype by altering key genes involved in extracellular matrix (ECM) remodeling in vivo. Results Herein, we unveiled new conceptual and functional pathophysiological avenues in GBM, with potential therapeutic implications, by demonstrating a novel dual role of miR-7 on the regulation of metabolism, through the impairment of the mitochondrial function and glycolysis, and autophagy, by inducing the initiation process through the regulation of PI3K/AKT/mTORC1 signaling, while blocking later stages via posttranscriptional inhibition of two key SNARE proteins, STX17 and SNAP29. Furthermore, in vivo studies using a preclinical model showed that miR-7 overexpression in already established GBM tumors promotes a significant inhibition of tumor size and progression and replicates the metabolic defects found in vitro. Moreover, our novel findings indicate that miR-7 modifies the tumor phenotype by promoting alterations in its mechanism of extracellular matrix remodeling in vivo. Conclusion Altogether, our study provides solid, convincing evidence demonstrating that miR-7 might be used as a promising therapeutic target for GBM, paving the way to explore its potential as novel biomarker and actionable target candidate for this lethal cancer. |
| format | Article |
| id | doaj-art-1e87c0776dc742a196de67095c85ec79 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
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| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-1e87c0776dc742a196de67095c85ec792025-08-20T03:46:15ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-08-0144112510.1186/s13046-025-03504-6MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodelingMarta Torrecilla-Parra0Virginia Pardo-Marqués1Antonio C. Fuentes-Fayos2Miguel E. G-García3Mario Fernández-de Frutos4José L. López-Aceituno5Cristina Puigdueta6Carmen Zamora7Ana Pérez-García8Juan F. Aranda9Rebeca Busto10Manuel D. Gahete11Raúl M. Luque12Cristina M. Ramírez13IMDEA Research Institute of Food & Health SciencesIMDEA Research Institute of Food & Health SciencesMaimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University HospitalMaimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University HospitalIMDEA Research Institute of Food & Health SciencesIMDEA Research Institute of Food & Health SciencesIMDEA Research Institute of Food & Health SciencesIMDEA Research Institute of Food & Health SciencesIMDEA Research Institute of Food & Health SciencesDepartment of Genetics, Physiology and Microbiology, Faculty of Biology, Complutense, University of MadridDepartment of Biochemistry-Research, Hospital Universitario Ramón y Cajal, IRYCISMaimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University HospitalMaimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University HospitalIMDEA Research Institute of Food & Health SciencesAbstract Background Due to the poor prognosis of patients suffering malignant brain tumors such as glioblastoma multiforme (GBM), the search for new therapeutic strategies with more efficacy and higher survival rate is of utmost urgency. Growing evidence suggests that alterations in autophagy and metabolism critically contribute to the pathogenesis and progression of GBM. In this context, microRNAs are known to regulate autophagy and associated cellular functions, which point them as promising therapeutic candidates. We previously established the role of miR-7 in regulating relevant metabolic pathways related to insulin signaling and cholesterol homeostasis. Methods Bioinformatics analysis was performed to identify miR-7 target genes potentially involved in the regulation of metabolism and cellular processes related to GBM. Ectopic expression of miR-7 was assessed to investigate its role in macroautophagy and energy metabolism. In vivo, miR-7 levels were restored in a mouse GBM xenograft model to evaluate its potential therapeutic effect in already established tumors. Additional mechanistic approaches, including transcriptomics, bioinformatics, and histopathological analyses, indicate that miR-7 modifies the tumor phenotype by altering key genes involved in extracellular matrix (ECM) remodeling in vivo. Results Herein, we unveiled new conceptual and functional pathophysiological avenues in GBM, with potential therapeutic implications, by demonstrating a novel dual role of miR-7 on the regulation of metabolism, through the impairment of the mitochondrial function and glycolysis, and autophagy, by inducing the initiation process through the regulation of PI3K/AKT/mTORC1 signaling, while blocking later stages via posttranscriptional inhibition of two key SNARE proteins, STX17 and SNAP29. Furthermore, in vivo studies using a preclinical model showed that miR-7 overexpression in already established GBM tumors promotes a significant inhibition of tumor size and progression and replicates the metabolic defects found in vitro. Moreover, our novel findings indicate that miR-7 modifies the tumor phenotype by promoting alterations in its mechanism of extracellular matrix remodeling in vivo. Conclusion Altogether, our study provides solid, convincing evidence demonstrating that miR-7 might be used as a promising therapeutic target for GBM, paving the way to explore its potential as novel biomarker and actionable target candidate for this lethal cancer.https://doi.org/10.1186/s13046-025-03504-6GBMMiR-7AutophagyMetabolismECM |
| spellingShingle | Marta Torrecilla-Parra Virginia Pardo-Marqués Antonio C. Fuentes-Fayos Miguel E. G-García Mario Fernández-de Frutos José L. López-Aceituno Cristina Puigdueta Carmen Zamora Ana Pérez-García Juan F. Aranda Rebeca Busto Manuel D. Gahete Raúl M. Luque Cristina M. Ramírez MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling Journal of Experimental & Clinical Cancer Research GBM MiR-7 Autophagy Metabolism ECM |
| title | MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling |
| title_full | MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling |
| title_fullStr | MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling |
| title_full_unstemmed | MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling |
| title_short | MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling |
| title_sort | mir 7 inhibits progression of glioblastoma by impairing autophagy resolution energy metabolism and ecm remodeling |
| topic | GBM MiR-7 Autophagy Metabolism ECM |
| url | https://doi.org/10.1186/s13046-025-03504-6 |
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