Systematically profiling the expression of eIF3 subunits in glioma reveals the expression of eIF3i has prognostic value in IDH-mutant lower grade glioma

BackgroundAbnormal expression of the eukaryotic initiation factor 3 (eIF3) subunits plays critical roles in tumorigenesis and progression, and also has potential prognostic value in cancers. However, the expression and clinical implications of eIF3 subunits in glioma remain unknown.MethodsExpression data of eIF3 for patients with gliomas were obtained from the Chinese Glioma Genome Atlas (CGGA) (n = 272) and The Cancer Genome Atlas (TCGA) (n = 595). Cox regression, the receiver operating characteristic (ROC) curves and Kaplan–Meier analysis were used to study the prognostic value. Gene oncology (GO) and gene set enrichment analysis (GSEA) were utilized for functional prediction.ResultsIn both the CGGA and TCGA datasets, the expression levels of eIF3d, eIF3e, eIF3f, eIF3h and eIF3l highly were associated with the IDH mutant status of gliomas. The expression of eIF3b, eIF3i, eIF3k and eIF3m was increased with the tumor grade, and was associated with poorer overall survival [All Hazard ratio (HR) > 1 and P < 0.05]. By contrast, the expression of eIF3a and eIF3l was decreased in higher grade gliomas and was associated with better overall survival (Both HR < 1 and P < 0.05). Importantly, the expression of eIF3i (located on chromosome 1p) and eIF3k (Located on chromosome 19q) were the two highest risk factors in both the CGGA [eIF3i HR = 2.068 (1.425–3.000); eIF3k HR = 1.737 (1.166–2.588)] and TCGA [eIF3i HR = 1.841 (1.642–2.064); eIF3k HR = 1.521 (1.340–1.726)] databases. Among eIF3i, eIF3k alone or in combination, the expression of eIF3i was the more robust in stratifying the survival of glioma in various pathological subgroups. The expression of eIF3i was an independent prognostic factor in IDH-mutant lower grade glioma (LGG) and could also predict the 1p/19q codeletion status of IDH-mutant LGG. Finally, GO and GSEA analysis showed that the elevated expression of eIF3i was significantly correlated with the biological processes of cell proliferation, mRNA processing, translation, T cell receptor signaling, NF-κB signaling and others.ConclusionsOur study reveals the expression alterations during glioma progression, and highlights the prognostic value of eIF3i in IDH-mutant LGG.

[1]  Hideo Nakamura,et al.  Prognostic relevance of genetic alterations in diffuse lower-grade gliomas , 2018, Neuro-oncology.

[2]  T. Jiang,et al.  m6A RNA methylation regulators contribute to malignant progression and have clinical prognostic impact in gliomas , 2019, Aging.

[3]  J. Walling,et al.  Detailed longitudinal sampling of glioma stem cells in situ reveals Chr7 gain and Chr10 loss as repeated events in primary tumor formation and recurrence , 2017, International journal of cancer.

[4]  Mustafa Khasraw,et al.  Advances in the Treatment of Malignant Gliomas , 2010, Current oncology reports.

[5]  G. Reifenberger,et al.  The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary , 2016, Acta Neuropathologica.

[6]  [World Health Organization classification of tumours of the central nervous system: a summary]. , 2016, Zhonghua bing li xue za zhi = Chinese journal of pathology.

[7]  T. Jiang,et al.  Combinations of four or more CpGs methylation present equivalent predictive value for MGMT expression and temozolomide therapeutic prognosis in gliomas , 2018, CNS neuroscience & therapeutics.

[8]  M. J. van den Bent,et al.  1p/19q loss within oligodendroglioma is predictive for response to first line temozolomide but not to salvage treatment. , 2006, European journal of cancer.

[9]  Jian-Ting Zhang,et al.  EIF3i Promotes Colon Oncogenesis by Regulating COX-2 Protein Synthesis and β-Catenin Activation , 2013, Oncogene.

[10]  L. Penalva,et al.  RNA processing as an alternative route to attack glioblastoma , 2017, Human Genetics.

[11]  Jennie W. Taylor,et al.  Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT , 2017, Acta Neuropathologica.

[12]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. , 2012, Neuro-oncology.

[13]  D. Louis,et al.  Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. , 1998, Journal of the National Cancer Institute.

[14]  Walter J. Curran,et al.  Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. , 2016, The New England journal of medicine.

[15]  Alexander R. Pico,et al.  Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. , 2015, The New England journal of medicine.

[16]  Steven J. M. Jones,et al.  Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. , 2015, The New England journal of medicine.

[17]  Xiangrong Song,et al.  eIF3i activity is critical for endothelial cells in tumor induced angiogenesis through regulating VEGFR and ERK translation , 2017, Oncotarget.

[18]  K. Aldape,et al.  Initial treatment patterns over time for anaplastic oligodendroglial tumors. , 2012, Neuro-oncology.

[19]  Wei Zhu,et al.  The function and clinical significance of eIF3 in cancer. , 2018, Gene.

[20]  Tao Jiang,et al.  Understanding high grade glioma: molecular mechanism, therapy and comprehensive management. , 2013, Cancer letters.

[21]  T. Jiang,et al.  A novel analytical model of MGMT methylation pyrosequencing offers improved predictive performance in patients with gliomas , 2018, Modern Pathology.

[22]  Hilde van der Togt,et al.  Publisher's Note , 2003, J. Netw. Comput. Appl..

[23]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[24]  J. Barnholtz-Sloan,et al.  CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009-2013. , 2016, Neuro-oncology.

[25]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[26]  M. Hassel,et al.  Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial. , 2018, European journal of cancer.

[27]  J. Hershey.  The role of eIF3 and its individual subunits in cancer. , 2015, Biochimica et biophysica acta.

[28]  Yuquan Wei,et al.  The Translation Initiation Factor eIF3i Up-regulates Vascular Endothelial Growth Factor A, Accelerates Cell Proliferation, and Promotes Angiogenesis in Embryonic Development and Tumorigenesis* , 2014, The Journal of Biological Chemistry.

[29]  R. Verhaak,et al.  Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma , 2017, Neuro-oncology.

[30]  Bin Zhou,et al.  Integrated genomic characterization of cancer genes in glioma , 2017, Cancer Cell International.

[31]  Yan-wei Liu,et al.  A novel gene signature based on five glioblastoma stem-like cell relevant genes predicts the survival of primary glioblastoma , 2018, Journal of Cancer Research and Clinical Oncology.

[32]  Lucy F. Stead,et al.  A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer , 2016, Clinical Cancer Research.

[33]  J. Cate,et al.  eIF3 targets cell proliferation mRNAs for translational activation or repression , 2015, Nature.

[34]  Rafaela Lacerda,et al.  eIF3: a factor for human health and disease , 2018, RNA biology.

[35]  D. Ruggero,et al.  Protein and Nucleotide Biosynthesis Are Coupled by a Single Rate-Limiting Enzyme, PRPS2, to Drive Cancer , 2014, Cell.

[36]  Y. Jou,et al.  Overexpressed‐eIF3I interacted and activated oncogenic Akt1 is a theranostic target in human hepatocellular carcinoma , 2013, Hepatology.

[37]  Yu Wang,et al.  CGCG clinical practice guidelines for the management of adult diffuse gliomas. , 2016, Cancer letters.

[38]  Jie Jin,et al.  FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase. , 2017, Cancer cell.

[39]  Wei Zhang,et al.  eIF3a: A new anticancer drug target in the eIF family. , 2018, Cancer letters.