Construction and Verification of an RNA-Binding Protein-Associated Prognostic Model for Gliomas

Abstract

Objective

To construct and verificate an RNA-binding protein (RBP)-associated prognostic model for gliomas using integrated bioinformatics analysis.

Methods

RNA-sequencing and clinic pathological data of glioma patients from The Cancer Genome Atlas (TCGA) database and the Chinese Glioma Genome Atlas database (CGGA) were downloaded. The aberrantly expressed RBPs were investigated between gliomas and normal samples in TCGA database. We then identified prognosis related hub genes and constructed a prognostic model. This model was further validated in the CGGA-693 and CGGA-325 cohorts.

Results

Totally 174 differently expressed genes-encoded RBPs were identified, containing 85 down-regulated and 89 up-regulated genes. We identified five genes-encoded RBPs (ERI1, RPS2, BRCA1, NXT1, and TRIM21) as prognosis related key genes and constructed a prognostic model. Overall survival (OS) analysis revealed that the patients in the high-risk subgroup based on the model were worse than those in the low-risk subgroup. The area under the receiver operator characteristic curve (AUC) of the prognostic model was 0.836 in the TCGA dataset and 0.708 in the CGGA-693 dataset, demonstrating a favorable prognostic model. Survival analyses of the five RBPs in the CGGA-325 cohort validated the findings. A nomogram was constructed based on the five genes and validated in the TCGA cohort, confirming a promising discriminating ability for gliomas.

Conclusion

The prognostic model of the five RBPs might serve as an independent prognostic algorithm for gliomas.

Keywords

bioinformatics analysis / glioma / prognostic model / RNA-binding protein

References

[1] KeeneJD. RNA regulons: coordination of posttranscriptional events. Nat Rev Genet, 2007, 8(7): 533-543

[2] TurnerM, Díaz-MuñozMD. RNA-binding proteins control gene expression and cell fate in the immune system. Nat Immunol, 2018, 19(2): 120-129

[3] HentzeMW, CastelloA, SchwarzlT, et al.. A brave new world of RNA-binding proteins. Nat Rev Mol Cell Biol, 2018, 19(5): 327-341

[4] CorleyM, BurnsMC, YeoGW. How RNA-Binding Proteins Interact with RNA: Molecules and Mechanisms. Mol Cell, 2020, 78(1): 9-29

[5] BohnsackKE, BohnsackMT. RNA-Binding Proteins Chaperone Ribonucleoprotein Complex Assembly to Solve the RNA-Folding Problem. Cell, 2019, 179(6): 1248-1250

[6] MarxV. Profiling the dress codes of RNA-binding proteins. Nat Methods, 2018, 15(9): 655-658

[7] YeJ, BlellochR. Regulation of pluripotency by RNA binding proteins. Cell Stem Cell, 2014, 15(3): 271-280

[8] ChénardCA, RichardS. New implications for the QUAKING RNA binding protein in human disease. J Neurosci Res, 2008, 86(2): 233-242

[9] NeelamrajuY, Gonzalez-PerezA, Bhat-NakshatriP, et al.. Mutational landscape of RNA-binding proteins in human cancers. RNA Biol, 2018, 15(1): 115-129

[10] MajumderP, ChuJF, ChatterjeeB, et al.. Co-regulation of mRNA translation by TDP-43 and Fragile X Syndrome protein FMRP. Acta Neuropathol, 2016, 132(5): 721-738

[11] WangGS, CooperTA. Splicing in disease: disruption of the splicing code and the decoding machinery. Nat Rev Genet, 2007, 8(10): 749-761

[12] OstromQT, GittlemanH, TruittG, et al.. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011–2015. Neuro-oncology, 2018, 20(suppl_4): iv1-iv86

[13] LouisDN, PerryA, ReifenbergerG, et al.. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol, 2016, 131(6): 803-820

[14] CorreaBR, De AraujoPR, QiaoM, et al.. Functional genomics analyses of RNA-binding proteins reveal the splicing regulator SNRPB as an oncogenic candidate in glioblastoma. Genome Biol, 2016, 17(1): 125

[15] CheungHC, HaiT, ZhuW, et al.. Splicing factors PTBP1 and PTBP2 promote proliferation and migration of glioma cell lines. Brain, 2009, 132(Pt8): 2277-2288

[16] GerstbergerS, HafnerM, TuschlT. A census of human RNA-binding proteins. Nat Rev Genet, 2014, 15(12): 829-845

[17] WenPY, ReardonDA. Neuro-oncology in 2015: Progress in glioma diagnosis, classification and treatment. Nat Rev Neurol, 2016, 12(2): 69-70

[18] MesratiMH, BehroozAB, AbuhamadAY, et al.. Understanding Glioblastoma Biomarkers: Knocking a Mountain with a Hammer. Cells, 2020, 9(5): 1236

[19] Delgado-MartínB, MedinaM. Advances in the Knowledge of the Molecular Biology of Glioblastoma and Its Impact in Patient Diagnosis, Stratification, and Treatment. Adv Sci (Weinh), 2020, 7(9): 1902971

[20] RiveraAL, PelloskiCE, GilbertMR, et al.. MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. Neurooncology, 2010, 12(2): 116-121

[21] ZhangC, MooreLM, LiX, et al.. IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma. Neuro-oncology, 2013, 15(9): 1114

[22] SiegalT. Clinical Relevance of Prognostic and Predictive Molecular Markers in Gliomas. Adv Tech Stand Neurosurg, 2016, 43: 91-108

[23] PereiraB, BillaudM, AlmeidaR. RNA-Binding Proteins in Cancer: Old Players and New Actors. Trends Cancer, 2017, 3(7): 506-528

[24] WangJ, QiJ, HouX. Systematically Dissecting the Function of RNA-Binding Proteins During Glioma Progression. Front Genet, 2019, 10: 1394

[25] CaoS, ZhengJ, LiuX, et al.. FXR1 promotes the malignant biological behavior of glioma cells via stabilizing MIR17HG. J Exp Clin Cancer Res, 2019, 38(1): 37

[26] ZhaoZ, WangY, YunD, et al.. TRIM21 overexpression promotes tumor progression by regulating ^cell proliferation, cell migration and cell senescence in human glioma. Am J Cancer Res, 2020, 10(1): 114-130

[27] LeeJH, LiuR, LiJ, et al.. Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis. Nat Commun, 2017, 8(1): 949

[28] MacdonaldTJ, PollackIF, OkadaH, et al.. Progressionassociated genes in astrocytoma identified by novel microarray gene expression data reanalysis. Methods Mol Biol, 2007, 377: 203-222

[29] ChoJ, ParkJ, ShinSC, et al.. USP47 Promotes Tumorigenesis by Negative Regulation of p53 through Deubiquitinating Ribosomal Protein S2. Cancers (Basel), 2020, 12(5): 1137

[30] RasmussenRD, GajjarMK, TuckovaL, et al.. BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity. Nat Commun, 2016, 7: 13398