CSRP2 promotes the glioblastoma mesenchymal phenotype via p130Cas-mediated NF-κB and MAPK pathways.

IF 12.8 1区 医学 Q1 ONCOLOGY
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
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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.

CSRP2通过p130cas介导的NF-κB和MAPK途径促进胶质母细胞瘤间充质表型。
背景:富含半胱氨酸的蛋白2 (CSRP2)在包括细胞增殖和分化在内的多种生物过程中发挥作用。然而,CSRP2是否以及如何参与多形性胶质母细胞瘤(GBM)的恶性肿瘤,包括其前膜到间质转化(PMT),尚不清楚。方法:分析CSRP2在低级别和高级别胶质瘤中的表达情况,并在不同肿瘤数据库中对CSRP2高、低表达胶质瘤患者进行生存分析。采用实时荧光定量PCR (qRT-PCR)和western blotting (WB)检测CSRP2在GBM和对照脑组织中的表达。通过一系列体外和体内功能试验确定CSRP2在GBM中的功能。采用WB、共免疫沉淀(co-IP)和免疫荧光法测定CSRP2与p130Cas的关系。利用现有数据库中的基因集富集分析和KEGG富集分析分析CSRP2参与GBM进展的机制。WB检测CSRP2和PMT标记物、NF-κB和MAPK信号相关蛋白、凋亡相关蛋白之间的关系。微尺度热电泳法检测米托蒽醌(MTO)与CSRP2能否结合。在稳定过表达CSRP2的GBM细胞系中,通过一系列体外功能试验检测MTO功能,并通过WB分析MTO与PMT标志物、NF-κB和MAPK信号相关蛋白、凋亡相关蛋白的关系。结果:我们发现CSRP2在GBM,尤其是间充质GBM中表达显著升高,CSRP2高表达的胶质瘤患者可能预后较差。CSRP2在GBM细胞中的过表达促进了体外增殖、集落形成、迁移、侵袭、替莫唑胺耐药、PMT和体内肿瘤形成。而敲低CSRP2则有相反的效果。在机制上,我们发现CSRP2与p130Cas相互作用,从而调节NF-κB和MAPK信号通路。CSRP2过表达和敲低分别升高和降低p130Cas水平以及NF-κB和MAPK活性。p130Cas下调和NF-κB抑制均可逆转CSRP2过表达导致的PMT、NF-κB和MAPK活性升高。最后,我们发现MTO结合CSRP2并抑制CSRP2过表达对GBM细胞的恶性作用。结论:我们的研究结果表明,CSRP2通过激活p130cas介导的NF-κB和MAPK信号通路,促进GBM恶性肿瘤包括PMT和替莫唑胺耐药。抑制CSRP2功能,包括使用MTO,可能成为治疗GBM的新方法。
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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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