{"title":"CSRP2 promotes the glioblastoma mesenchymal phenotype via p130Cas-mediated NF-κB and MAPK pathways.","authors":"Jiawei He, Liang Zhang, Hao Xu, Chengtian Gao, Wentao Zhao, Bingchang Zhang, Wanhong Han, Wenpeng Zhao, Guowei Tan, Sifang Chen, Ping Zhong, Zhe Shen, Jian Meng, Ziqian Tang, Hanwen Lu, Xin Gao, Zhangyu Li, Wenhua Li, Jianyao Mao, Bosen Liu, Yun-Wu Zhang, Zhanxiang Wang","doi":"10.1186/s13046-025-03484-7","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Cysteine-rich protein 2 (CSRP2) plays a role in a variety of biological processes including cell proliferation and differentiation. However, whether and how CSRP2 participates in the malignancy of glioblastoma multiforme (GBM), including its proneural-to-mesenchymal transition (PMT), remains unclear.</p><p><strong>Methods: </strong>CSRP2 expression in low-grade and high-grade gliomas was analyzed, and survival analyses were performed in patients with gliomas with high and low CSRP2 expression in various tumor databases. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were used to detect the expression of CSRP2 in GBM and control brain tissues. CSRP2 function in GBM was determined by a series of functional tests in vitro and in vivo. WB, co-immunoprecipitation (co-IP) and immunofluorescence were used to determine the relation between CSRP2 and p130Cas. Mechanisms of CSRP2 involvement in GBM progression were analyzed with gene set enrichment analysis and KEGG enrichment analysis in available databases. WB was used to determine the relation between CSRP2 and PMT markers, NF-κB and MAPK signaling-related proteins, and apoptosis-related proteins. Microscale thermophoresis assay was used to analyze whether mitoxantrone (MTO) and CSRP2 could bind. MTO function was determined by a series of functional tests in vitro, while the relation between MTO and PMT markers, NF-κB and MAPK signaling-related proteins, and apoptosis-related proteins was analyzed by WB in GBM cell lines stably overexpressing CSRP2.</p><p><strong>Results: </strong>We found that CSRP2 expression significantly increased in GBM, especially mesenchymal GBM, and that glioma patients with high CSRP2 expression possibly had poor prognosis. CSRP2 overexpression in GBM cells promoted proliferation, colony formation, migration, invasion, temozolomide resistance, and PMT in vitro and tumor formation in vivo. While knockdown of CSRP2 had the opposite effects. Mechanistically, we revealed that CSRP2 interacted with p130Cas, thereby regulating the NF-κB and the MAPK signaling pathways. CSRP2 overexpression and knockdown increased and decreased p130Cas levels and NF-κB and MAPK activities, respectively. Both p130Cas downregulation and NF-κB inhibition reversed the elevated PMT and NF-κB and MAPK activities resulted from CSRP2 overexpression. Finally, we identified that MTO bound CSRP2 and inhibited the malignant effects of CSRP2 overexpression on GBM cells.</p><p><strong>Conclusions: </strong>Our findings demonstrate that CSRP2 promotes GBM malignancy including PMT and temozolomide resistance through activating p130Cas-mediated NF-κB and MAPK signaling pathways. Inhibiting CSRP2 function, including using MTO, may become a novel therapeutic approach for GBM.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"228"},"PeriodicalIF":12.8000,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323131/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental & Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13046-025-03484-7","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Cysteine-rich protein 2 (CSRP2) plays a role in a variety of biological processes including cell proliferation and differentiation. However, whether and how CSRP2 participates in the malignancy of glioblastoma multiforme (GBM), including its proneural-to-mesenchymal transition (PMT), remains unclear.
Methods: CSRP2 expression in low-grade and high-grade gliomas was analyzed, and survival analyses were performed in patients with gliomas with high and low CSRP2 expression in various tumor databases. Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were used to detect the expression of CSRP2 in GBM and control brain tissues. CSRP2 function in GBM was determined by a series of functional tests in vitro and in vivo. WB, co-immunoprecipitation (co-IP) and immunofluorescence were used to determine the relation between CSRP2 and p130Cas. Mechanisms of CSRP2 involvement in GBM progression were analyzed with gene set enrichment analysis and KEGG enrichment analysis in available databases. WB was used to determine the relation between CSRP2 and PMT markers, NF-κB and MAPK signaling-related proteins, and apoptosis-related proteins. Microscale thermophoresis assay was used to analyze whether mitoxantrone (MTO) and CSRP2 could bind. MTO function was determined by a series of functional tests in vitro, while the relation between MTO and PMT markers, NF-κB and MAPK signaling-related proteins, and apoptosis-related proteins was analyzed by WB in GBM cell lines stably overexpressing CSRP2.
Results: We found that CSRP2 expression significantly increased in GBM, especially mesenchymal GBM, and that glioma patients with high CSRP2 expression possibly had poor prognosis. CSRP2 overexpression in GBM cells promoted proliferation, colony formation, migration, invasion, temozolomide resistance, and PMT in vitro and tumor formation in vivo. While knockdown of CSRP2 had the opposite effects. Mechanistically, we revealed that CSRP2 interacted with p130Cas, thereby regulating the NF-κB and the MAPK signaling pathways. CSRP2 overexpression and knockdown increased and decreased p130Cas levels and NF-κB and MAPK activities, respectively. Both p130Cas downregulation and NF-κB inhibition reversed the elevated PMT and NF-κB and MAPK activities resulted from CSRP2 overexpression. Finally, we identified that MTO bound CSRP2 and inhibited the malignant effects of CSRP2 overexpression on GBM cells.
Conclusions: Our findings demonstrate that CSRP2 promotes GBM malignancy including PMT and temozolomide resistance through activating p130Cas-mediated NF-κB and MAPK signaling pathways. Inhibiting CSRP2 function, including using MTO, may become a novel therapeutic approach for GBM.
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.