Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3.
Splicing machinery dysregulation drives glioblastoma development/aggressiveness: oncogenic role of SRSF3.
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DOI：
10.1093/brain/awaa273
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发表时间：
2020-12-05
期刊：
影响因子：
--
通讯作者：
Luque RM
中科院分区：
文献类型：
--
作者：
Fuentes-Fayos AC;Vázquez-Borrego MC;Jiménez-Vacas JM;Bejarano L;Pedraza-Arévalo S;L-López F;Blanco-Acevedo C;Sánchez-Sánchez R;Reyes O;Ventura S;Solivera J;Breunig JJ;Blasco MA;Gahete MD;Castaño JP;Luque RM
Fuentes-Fayos等人表明，剪接体组分和剪接因子的表达在高级别星形细胞瘤和胶质母细胞瘤中失调。剪接机制可能是诊断和预后生物标志物以及治疗靶点的新来源，SRSF 3是胶质母细胞瘤中的关键剪接因子。胶质母细胞瘤仍然是最致命的脑肿瘤，从诊断开始存活12-16个月。因此，迫切需要鉴定新的诊断、预后和治疗工具来应对胶质母细胞瘤。新出现的证据表明，控制剪接过程（剪接体）的细胞机制在肿瘤中发生改变，导致与肿瘤进展和侵袭性相关的致癌剪接事件。在此，我们首次发现了相关剪接体成分和剪接因子表达的严重失调。与健康脑对照样品相比，在充分表征的人类高级星形细胞瘤（主要是胶质母细胞瘤）的群组中，SRSF 3、RBM 22、PTBP 1和RBM 3能够完美区分肿瘤和对照样品，以及前神经样或间充质样肿瘤与来自不同胶质瘤小鼠模型的对照样品之间的差异。结果在另外四个独立的人类队列中得到证实。SRSF 3、RBM 22、PTBP 1和RBM 3的沉默降低了体外侵袭性参数（例如增殖、迁移、肿瘤球形成等）。并诱导细胞凋亡，尤其是SRSF 3。值得注意的是，SRSF 3与患者生存率和相关肿瘤标志物相关，其体内沉默可能通过涉及PDGFRB和相关致癌信号传导途径（PI 3 K-AKT/ERK）的分子/细胞机制大幅降低肿瘤发生和进展，这也可能涉及控制PDGFRB的特定转录因子（即TP 73）的选择性剪接事件的明显改变。总之，我们的研究结果证明了胶质母细胞瘤中与剪接机制相关的分子失调，这可能被认为是胶质母细胞瘤新的诊断和预后生物标志物以及治疗靶点的来源。值得注意的是，SRSF 3与胶质母细胞瘤的发展、进展、侵袭性和患者生存直接相关，代表了一种新的潜在治疗靶点来解决这种破坏性病理。
Fuentes-Fayos et al. show that the expression of spliceosome components and splicing factors is dysregulated in high-grade astrocytomas and glioblastomas. The splicing machinery could be a new source of diagnostic and prognostic biomarkers as well as therapeutic targets, with SRSF3 being a key splicing factor in glioblastomas. Glioblastomas remain the deadliest brain tumour, with a dismal ∼12–16-month survival from diagnosis. Therefore, identification of new diagnostic, prognostic and therapeutic tools to tackle glioblastomas is urgently needed. Emerging evidence indicates that the cellular machinery controlling the splicing process (spliceosome) is altered in tumours, leading to oncogenic splicing events associated with tumour progression and aggressiveness. Here, we identify for the first time a profound dysregulation in the expression of relevant spliceosome components and splicing factors (at mRNA and protein levels) in well characterized cohorts of human high-grade astrocytomas, mostly glioblastomas, compared to healthy brain control samples, being SRSF3, RBM22, PTBP1 and RBM3 able to perfectly discriminate between tumours and control samples, and between proneural-like or mesenchymal-like tumours versus control samples from different mouse models with gliomas. Results were confirmed in four additional and independent human cohorts. Silencing of SRSF3, RBM22, PTBP1 and RBM3 decreased aggressiveness parameters in vitro (e.g. proliferation, migration, tumorsphere-formation, etc.) and induced apoptosis, especially SRSF3. Remarkably, SRSF3 was correlated with patient survival and relevant tumour markers, and its silencing in vivo drastically decreased tumour development and progression, likely through a molecular/cellular mechanism involving PDGFRB and associated oncogenic signalling pathways (PI3K-AKT/ERK), which may also involve the distinct alteration of alternative splicing events of specific transcription factors controlling PDGFRB (i.e. TP73). Altogether, our results demonstrate a drastic splicing machinery-associated molecular dysregulation in glioblastomas, which could potentially be considered as a source of novel diagnostic and prognostic biomarkers as well as therapeutic targets for glioblastomas. Remarkably, SRSF3 is directly associated with glioblastoma development, progression, aggressiveness and patient survival and represents a novel potential therapeutic target to tackle this devastating pathology.
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