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SRPK1通过激活Wnt/β-连环蛋白和JAK-2/STAT-3信号通路促进胶质瘤的增殖、迁移和侵袭。

SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/β-Catenin and JAK-2/STAT-3 Signaling Pathways.

作者信息

Shi Mengna, Sun Dan, Deng Lu, Liu Jing, Zhang Min-Jie

机构信息

Department of Oncology, Wenzhou Medical University, Wenzhou 325027, China.

Department of Neurosurgery, The First Affiliated Hospital of Anhui University of Science and Technology (Huainan First People's Hospital), Huainan 232002, China.

出版信息

Biomedicines. 2024 Feb 6;12(2):378. doi: 10.3390/biomedicines12020378.

Abstract

Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/β-catenin (wingless-int1/β-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of β-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/β-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients.

摘要

目前,胶质瘤的治疗仍主要依赖于手术及放化疗。尽管有多种药物可供使用,包括替莫唑胺,但总体治疗效果仍不尽人意,预后依然较差。因此,深入研究胶质瘤的发生发展机制并寻找新的治疗靶点是改善胶质瘤治疗效果及提高患者预后的关键。免疫组化用于检测组织中相关分子的表达,qPCR和蛋白质免疫印迹用于检测相关分子的mRNA和蛋白质表达,CCK-8(细胞计数试剂盒-8)用于评估细胞活力和增殖能力,Transwell用于评估细胞迁移和侵袭能力,RNA转录组测序用于识别最具影响力的信号通路。SRPK1(丝氨酸/精氨酸富集蛋白特异性激酶1)在胶质瘤中高表达,但在正常组织中不表达。其表达与胶质瘤的分级呈正相关,与预后呈负相关。SRPK1显著促进胶质瘤的发生发展。敲低SRPK1导致胶质瘤的增殖、迁移和侵袭能力显著下降。SRPK1表达缺失诱导G2/M期阻滞和有丝分裂灾难,导致细胞凋亡。SRPK1的过表达激活Wnt/β-连环蛋白(无翅型MMTV整合位点家族成员1/β-连环蛋白)和JAK-2/STAT-3(Janus激酶2/信号转导子和转录激活子3)信号通路,促进胶质瘤的增殖、迁移和侵袭。SRPK1的过表达挽救了由β-连环蛋白或JAK-2沉默引起的细胞增殖、迁移和侵袭能力降低。构建了稳定的shRNA-LN229细胞系,并利用裸鼠模型发现,稳定敲除SRPK1显著降低了胶质瘤细胞的致瘤能力,裸鼠皮下肿瘤体积和重量显著减小证明了这一点。我们已经证明SRPK1在胶质瘤中高表达。SRPK1的过表达激活Wnt/β-连环蛋白和JAK-2/STAT-3信号通路,促进胶质瘤的增殖、迁移和侵袭。沉默与SRPK1相关的信号通路可能为胶质瘤患者提供潜在的治疗选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f152/10886746/62b69e7b1234/biomedicines-12-00378-g001.jpg

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