DUSP8 as a regulator of glioblastoma stem-like cell contribution to tumor vascularization.

IF 12.8 1区 医学 Q1 ONCOLOGY
Giorgia Castellani, Mariachiara Buccarelli, Quintino Giorgio D'Alessandris, Gabriele De Luca, Ramona Ilari, Francesca Pedini, Maurizio Martini, Cristiana Mollinari, Claudio Tabolacci, Gabriele Ricciardi, Emanuela Germanà, Valentina Lulli, Alessandra Boe, Mauro Biffoni, Giovanna Marziali, Roberto Pallini, Lucia Ricci-Vitiani
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Abstract

Glioblastomas (GBMs) are highly vascularized cancers. Transdifferentiation of GBM stem-like cells (GSCs) into GSC-derived endothelial cells (GdECs) contributes to GBM neovascularization. To dissect the molecular mechanisms and the signaling pathways underlying GSC contribution to tumor vascularization, we identified a three miRNA signature able to discriminate GSCs from GdECs by regulating different signaling pathways. DUSP8 resulted as the common target of the miRNA signature identified and is negatively regulated by miR-1825. DUSP8 is emerging as a critical negative regulator MAPKs pathway and is involved in cell oxidative stress response and apoptosis, as well as, in several diseases, including cancer. In GBM patients, DUSP8 and miR-1825 expression are inversely correlated and DUSP8 down-regulation is significantly associated with higher microvascular density and poor overall survival. Exploring the impact of DUSP8 in GSC transdifferentiation, we demonstrated that DUSP8 down-regulation interferes with MAPK pathway and affects soluble factor release. In vitro DUSP8 modulation experiments showed that DUSP8 enforced expression impairs GdEC ability to form tube-like structures. Gene expression variations induced by DUSP8 modulation affect transcripts associated with EMT pathway, confirming that DUSP8 shutdown and, therefore, the activation of MAPK pathway, is mandatory to GSC transdifferentiation. In vivo experiments demonstrated that both DUSP8 enforced expression and silencing dramatically affect gliomagenesis. Dissecting the molecular mechanisms underlying the contribution of GSCs to tumor angiogenesis might represent a chance to develop new and more efficient antiangiogenic therapeutic protocols for GBM treatment. Our findings provide a strong rationale to develop therapeutic strategies based on modulation of DUSP8 for GBM treatment.

DUSP8作为胶质母细胞瘤干细胞样细胞对肿瘤血管化贡献的调节因子。
胶质母细胞瘤(GBMs)是高度血管化的癌症。GBM干细胞样细胞(GSCs)转分化为gsc来源的内皮细胞(GdECs)有助于GBM新生血管的形成。为了剖析GSC对肿瘤血管化的分子机制和信号通路,我们发现了三个miRNA特征,能够通过调节不同的信号通路来区分GSC和GdECs。DUSP8作为鉴定的miRNA特征的共同靶标,受到miR-1825的负调控。DUSP8是一个关键的负调控MAPKs通路,参与细胞氧化应激反应和细胞凋亡,以及包括癌症在内的几种疾病。在GBM患者中,DUSP8与miR-1825表达呈负相关,DUSP8下调与微血管密度升高和总生存期差显著相关。我们研究了DUSP8在GSC转分化中的作用,发现DUSP8下调可干扰MAPK通路,影响可溶性因子释放。体外DUSP8调控实验表明,DUSP8的强制表达削弱了GdEC形成管状结构的能力。DUSP8调控诱导的基因表达变异影响EMT通路相关转录本,证实DUSP8的关闭以及MAPK通路的激活对于GSC转分化是必需的。体内实验表明DUSP8的强制表达和沉默都会显著影响胶质瘤的形成。剖析GSCs对肿瘤血管生成的分子机制可能为GBM治疗开发新的更有效的抗血管生成治疗方案提供机会。我们的研究结果为开发基于DUSP8调节的GBM治疗策略提供了强有力的理论依据。
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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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