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。

IF 12.8 1区 医学 Q1 ONCOLOGY
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
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引用次数: 0

摘要

背景:由于多形性胶质母细胞瘤(GBM)等恶性脑肿瘤患者预后较差,寻找疗效更好、生存率更高的治疗策略迫在眉睫。越来越多的证据表明,自噬和代谢的改变对GBM的发病和进展起着至关重要的作用。在这种情况下,已知microrna调节自噬和相关的细胞功能,这表明它们是有希望的治疗候选者。我们之前确定了miR-7在调节与胰岛素信号传导和胆固醇稳态相关的代谢途径中的作用。方法:通过生物信息学分析,鉴定miR-7靶基因可能参与调节与GBM相关的代谢和细胞过程。我们评估了miR-7的异位表达,以研究其在巨噬和能量代谢中的作用。在体内,在小鼠GBM异种移植模型中恢复miR-7水平,以评估其对已经建立的肿瘤的潜在治疗作用。其他机制方法,包括转录组学、生物信息学和组织病理学分析,表明miR-7通过改变体内参与细胞外基质(ECM)重塑的关键基因来改变肿瘤表型。结果:在此,我们揭示了GBM中新的概念和功能病理生理途径,具有潜在的治疗意义,通过证明miR-7在调节代谢方面的新双重作用,通过线粒体功能和糖酵解的损伤,以及自噬,通过调节PI3K/AKT/mTORC1信号传导诱导起始过程,同时通过转录后抑制两个关键SNARE蛋白STX17和SNAP29来阻断后期阶段。此外,使用临床前模型的体内研究表明,miR-7在已经建立的GBM肿瘤中的过表达促进了肿瘤大小和进展的显著抑制,并复制了体外发现的代谢缺陷。此外,我们的新发现表明,miR-7通过促进体内细胞外基质重塑机制的改变来改变肿瘤表型。结论:总之,我们的研究提供了坚实的、令人信服的证据,证明miR-7可能被用作GBM的有希望的治疗靶点,为探索其作为这种致命癌症的新型生物标志物和可操作靶点候选物的潜力铺平了道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
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. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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