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
{"title":"MiR-7通过损害自噬分辨率、能量代谢和ECM重塑来抑制胶质母细胞瘤的进展。","authors":"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","doi":"10.1186/s13046-025-03504-6","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"237"},"PeriodicalIF":12.8000,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351809/pdf/","citationCount":"0","resultStr":"{\"title\":\"MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling.\",\"authors\":\"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\",\"doi\":\"10.1186/s13046-025-03504-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":50199,\"journal\":{\"name\":\"Journal of Experimental & Clinical Cancer Research\",\"volume\":\"44 1\",\"pages\":\"237\"},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2025-08-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351809/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Experimental & Clinical Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s13046-025-03504-6\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental & Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13046-025-03504-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
MiR-7 inhibits progression of glioblastoma by impairing autophagy resolution, energy metabolism and ECM remodeling.
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.
期刊介绍:
The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications.
We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options.
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