{"title":"Clusterin facilitates glioma progression via BCL2L1-dependent regulation of apoptotic resistance.","authors":"Qingqing Xu, Xin Liu, Yibo Zhang, Shiyu Yuan, Wenli Huang, Mingshan Pi, Qi Xiong, Hongyan Zhou, Yuran Gui, Yifan Xiao, Xiaochuan Wang, Xiji Shu, Yiyuan Xia","doi":"10.3389/fnmol.2025.1596021","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Clusterin (CLU) is a multifunctional protein involved in various pathophysiological processes and diseases. Glioma, the most common aggressive primary brain tumor, is characterized by high morbidity, mortality, and extremely poor prognosis. Our research has found that CLU is upregulated in glioma and contributes to increased tumor malignancy. However, the specific regulatory mechanisms of CLU in the context of glioma are not fully understood.</p><p><strong>Methods: </strong>We used glioma public databases, immunohistochemistry (IHC), and immunoblotting techniques to evaluate the expression levels and prognostic value of CLU in glioma. Cell migration and proliferation assays, including the scratch wound healing and MTT assays, were conducted to assess the functional impact of CLU. In addition, immunoblotting and flow cytometry were used to analyze apoptosis-related proteins and CLU-BCL2L1 interactions. An <i>in situ</i> tumor model using nude mice was established to investigate the effects of CLU <i>in vivo</i>.</p><p><strong>Results: </strong>Bioinformatics analyses showed that CLU was highly expressed in glioma, associated with poor clinical outcomes. Functional assays revealed that CLU and BCL2L1 promoted glioma cell migration and proliferation. Silencing CLU reduced the migration and proliferation of glioma cells, while overexpression of CLU enhanced these aggressive phenotypes. Mechanistic studies showed CLU regulated BCL2L1 expression, inhibiting apoptosis pathways and promoting malignancy. <i>In vivo</i> experiments confirmed the inhibitory effects of CLU downregulation on glioma growth.</p><p><strong>Conclusion: </strong>This study clarifies the role of the CLU-BCL2L1 axis in promoting glioma migration and proliferation both <i>in vitro</i> and <i>in vivo</i>. It suggests that targeting this pathway may be a promising therapeutic strategy for glioma.</p>","PeriodicalId":12630,"journal":{"name":"Frontiers in Molecular Neuroscience","volume":"18 ","pages":"1596021"},"PeriodicalIF":3.8000,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12216978/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Molecular Neuroscience","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3389/fnmol.2025.1596021","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Clusterin (CLU) is a multifunctional protein involved in various pathophysiological processes and diseases. Glioma, the most common aggressive primary brain tumor, is characterized by high morbidity, mortality, and extremely poor prognosis. Our research has found that CLU is upregulated in glioma and contributes to increased tumor malignancy. However, the specific regulatory mechanisms of CLU in the context of glioma are not fully understood.
Methods: We used glioma public databases, immunohistochemistry (IHC), and immunoblotting techniques to evaluate the expression levels and prognostic value of CLU in glioma. Cell migration and proliferation assays, including the scratch wound healing and MTT assays, were conducted to assess the functional impact of CLU. In addition, immunoblotting and flow cytometry were used to analyze apoptosis-related proteins and CLU-BCL2L1 interactions. An in situ tumor model using nude mice was established to investigate the effects of CLU in vivo.
Results: Bioinformatics analyses showed that CLU was highly expressed in glioma, associated with poor clinical outcomes. Functional assays revealed that CLU and BCL2L1 promoted glioma cell migration and proliferation. Silencing CLU reduced the migration and proliferation of glioma cells, while overexpression of CLU enhanced these aggressive phenotypes. Mechanistic studies showed CLU regulated BCL2L1 expression, inhibiting apoptosis pathways and promoting malignancy. In vivo experiments confirmed the inhibitory effects of CLU downregulation on glioma growth.
Conclusion: This study clarifies the role of the CLU-BCL2L1 axis in promoting glioma migration and proliferation both in vitro and in vivo. It suggests that targeting this pathway may be a promising therapeutic strategy for glioma.
期刊介绍：
Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.
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