Comprehensive Analysis of Prognostic Alternative Splicing Signatures in Oral Squamous Cell Carcinoma

Abstract

Background Alternative splicing (AS) plays an essential role in tumorigenesis and progression. This study aimed to develop a novel prognostic model based on the AS events to obtain more accurate survival prediction and search for potential therapeutic targets in oral squamous cell carcinoma (OSCC). Methods Seven types of AS events in 326 OSCC patients with RNA-seq were obtained from the TCGA SpliceSeq tool and the TCGA database. Cox analysis, the least absolute shrinkage and selection operator Cox regression and random forest were employed to establish prognostic models. Genomics of Drug Sensitivity in Cancer (GDSC) was adopted to estimate the possible drug sensiticity. Prognostic splicing factor (SF)-AS network was constructed by Cytoscape. Results The final model included 12 AS events, showing satisfactory performance. The area under the curve for 3- and 5-year survival in the training cohort was 0.83 and 0.82, respectively while that in internal validation was 0.83 and 0.82 accordingly. The calibration curve also indicated a satisfactory agreement between the observation and the predictive values. Low-risk patients stratified by the final model presented higher sensitivity to three chemo drugs. Besides, the prognostic SF-AS regulatory network contained five key SFs and 62 AS events. Conclusions We developed a powerful prognostic AS signature for OSCC and deepened the understanding of SF-AS network regulatory mechanisms. Low-risk patients tended to be more sensitive to the three chemo drugs while five key SFs including CELF2, TIA1, HNRNPC, HNRNPK, and SRSF9 were identified as potential prognostic biomarkers, which may offer new prospects for effective therapies of OSCC.

IQGAP1 and RNA Splicing in the Context of Head and Neck via Phosphoproteomics

“…Another investigation of HNSCC cell lines and tissues found MATR3, an RNA-binding protein and regulator of alternative splicing, to be upregulated in HNSCC. , Additionally, SRSF5, a splicing factor involved in constitutive splicing that can modulate the selection of alternative splice sites, has been shown to be upregulated in HNSCC tumors . Lower expression of SRSF9, another splicing factor similar to SRSF5, and RBMX, a protein implicated in alternative splicing that interacts with SRSF10, correlates with improved survival in HNSCC patients. − Searching the CPTAC HNSCC data also revealed that many of these splicing-related proteins have significantly altered phosphorylation levels between HNSCC tumors and normal tissue . Two of the significantly changing phosphosites in our NOKs data set (S853 in PRPF40B and S1424 in SRRM2) were significantly changed in the same direction between tumor and normal tissue as in the NOKs and NOKs IQGAP1KO (without significant change in the proteins).…”

Genome-Wide Analyses of Prognostic and Therapeutic Alternative Splicing Signatures in Bladder Urothelial Carcinoma

“…We also examined the profile and clinical relevance of AS events in BLCA by performing a pan-cancer analysis (26). Recently, some AS bioinformatics analyses reported the good performance of AS events in predicting prognosis (27)(28)(29). However, these studies have been based on SASEs, which explains their good prognosis-predicting performance.…”

CELF Family Proteins in Cancer: Highlights on the RNA-Binding Protein/Noncoding RNA Regulatory Axis

“…In addition, CELF2 has been identified as one of the hub splicing factors of prognostic splicing events, suggesting that these splicing factors might be used to treat glioma [84]. Moreover, in oral squamous cell carcinoma, CELF2 is identified as a promising prognostic biomarker [85].…”