Abstract
Despite many changes in alternative splicing events (ASEs) are frequently involved in various cancers, prognosis-related ASEs and drug treatment targets in glioblastoma multiforme (GBM) have not been well explored. ASEs participate in many biological behaviors in the initiation and progression of tumors, the aberrant ASE has been considered another hallmark of cancer, and the systematic study of alternative splicing may provide potential biomarkers for malignancies. In this study, we carried out a systematic analysis to characterize the ASE signatures in GBM cohort. Through comparing GBM tissues and nontumor tissues, a total of 48,191 differently expressed ASEs from 10,727 genes were obtained, and these aberrant ASEs play an important role in the oncogenic process. Then, we identified 514 ASEs independently associated with patient survival in GBM by univariate and multivariate Cox regression, including exon skip in CD3D, alternate acceptor site in POLD2, and exon skip in DCN. Those prognostic models built on ASEs of each splice type can accurately predict the outcome of GBM patients, and values for the area under curve were 0.97 in the predictive model based on alternate acceptor site. In addition, the splicing-regulatory network revealed an interesting correlation between survival-associated splicing factors and prognostic ASE corresponding genes. Moreover, these three hub splicing factors in splicing regulation network are the potential targets of some drugs. In conclusion, a systematic analysis of ASE signatures in GBM could serve as an indicator for identifying novel prognostic biomarkers and guiding clinical treatment.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive cancers in the central nervous system, and the 5-year overall survival rate of this disease is only 0.05% to 4.7% [1,2,3]
Increasing evidence suggested that the alternative splicing events (ASEs) were a posttranscriptional biological process, a predominant mechanism for RNA and protein diversity [32]. e specific dysregulation of splicing played critical roles in producing isoform to boost proliferation, cancer cell survival, drug resistance, and metastasis [12, 33, 34]
Scientists have found that high ECT2 splice variant including exon 5 (ECT2-Ex5+) levels was negatively related to prognosis in breast cancer treated with doxorubicin [36]
Summary
Glioblastoma multiforme (GBM) is the most aggressive cancers in the central nervous system, and the 5-year overall survival rate of this disease is only 0.05% to 4.7% [1,2,3]. Many alternative splicing events (ASEs) are closely related to biological activity, to physiological functions, such as cell development and differentiation [10], and to pathological processes, including cancer-associated phenotype [11]. Numerous genomic and functional studies have found that splicing defects and the production of specific isoforms are the drivers of cancer [12]. CircSMARCA5 is an upstream regulator of pro- to antiangiogenic VEGFA alternative splicing isoform ratio within GBM cells, and a highly promising GBM prognostic and prospective antiangiogenic molecule could be a prognostic biomarker and a therapeutic target [23]. Systematic analyses of alternative splicing in drugs therapeutic response in GBM have been lacking. Rough this method, we hope to find target markers to predict the prognosis and the therapeutic targets of GBM patients and further to guide clinical individualized treatment
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
