Identification of IGF2BP3 as an Adverse Prognostic Biomarker of Gliomas

Abstract

N6-methyladenosine (m6A) RNA modification can alter gene expression and function by regulating RNA splicing, stability, translocation, and translation. It is involved in various types of cancer. However, its role in gliomas is not well known. This study aimed to determine the prognostic value of the m6A RNA methylation regulator in gliomas and investigate the underlying mechanisms of the aberrant expression of m6A-related genes.mRNA expression profiles and clinical information of 448 glioma samples were obtained from The Cancer Genome Atlas and cBioportal. The expression of m6A-related genes in normal controls and low-grade glioma and glioblastoma was obtained from Gene Expression Profiling Interactive Analysis. Further, m6A-related gene expression and its relationship with prognosis were obtained through The Chinese Glioma Genome Atlas (CGGA). Multivariate Cox regression analyses were performed, and a nomogram was built with potential risk factors based on a multivariate Cox analysis to predict survival probability. Online tools such as Gene Set Enrichment Analysis, STRING, Cytoscape, and Molecular Complex Detection were applied for bioinformatics analysis and to investigate the underlying mechanisms of the aberrant expression of m6A-related genes. The multivariate Cox regression analysis found that higher expression levels of YTHDC2 and insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3, also called IMP3) were independent negative and positive prognostic factors for overall survival (OS), respectively. Data from the CGGA database showed that IGF2BP3 expression increased when the tumor grade increased. Receiver operating characteristic (ROC) curve was used to evaluate the predictive specificity and sensitivity. The area under the ROC curve indicated that the OS prediction was 0.92 (1-year) and 0.917 (3-years), indicating that m6A-related genes could predict patient survival. In addition, IGF2BP3 was closely related to the shorter survival period of patients. Copy number variation and DNA methylation, but not somatic mutations, might contribute to the abnormal upregulation of IGF2BP3 in gliomas. Significantly altered genes were identified, and the protein–protein interaction network was constructed. Based on the data presented, our study identified several m6A-related genes, especially IGF2BP3, that could be potential prognostic biomarkers of gliomas. The study unveiled the potential regulatory mechanism of IGF2BP3 in gliomas.

A Novel Splice Variant of BCAS1 Inhibits β-Arrestin 2 to Promote the Proliferation and Migration of Glioblastoma Cells, and This Effect Was Blocked by Maackiain

“…Similarly, SRSF7 can specifically regulate m6A of mRNA of PDZ binding kinase (PBK) to promote its AS response regulated by insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), which ultimately leads to GBM proliferation and migration [ 97 ]. IGF2BP3 has also been shown to be a biomarker for gliomas [ 98 ]. Probable ATP-dependent RNA helicase DDX46, involved in pre-mRNA splicing and upregulated in GBM, promotes cell proliferation by activating MAPK-p38 signaling [ 99 ].…”

IMP3 promotes re‐endothelialization after arterial injury via increasing stability of VEGF mRNAhv

“… 28 , 29 , 30 IMPs play its role in post‐translational RNA processing, such as transcript localization, translation and stabilization 31 , 32 , 33 ; additionally, IMPs family were recently identified as a family of m6A readers. 8 , 34 However, previous research mainly focussed on the biological functions of IMPs in tumours and embryogenesis. For example, IMP3 participates in RNA trafficking and stabilization which promotes cell proliferation, migration in tumour progression and metastasis.…”

“…IMP3, also known as insulin‐like growth factor 2 (IGF2) mRNA‐binding protein 3 (IGF2BP3), is a member of the insulin‐like growth factor 2 mRNA‐binding proteins family 28–30 . IMPs play its role in post‐translational RNA processing, such as transcript localization, translation and stabilization 31–33 ; additionally, IMPs family were recently identified as a family of m6A readers 8,34 . However, previous research mainly focussed on the biological functions of IMPs in tumours and embryogenesis.…”

The role and regulatory mechanism of m6A methylation in the nervous system

“…IGF2BP2 interacts with the CASC9/IGF2BP2 complex and accelerates aerobic glycolysis in GBM by regulating the mRNA of HK2. It was reported that high expression of IGF2BP3 in patients with glioma significantly reduced survival time, which was also associated with poor prognosis, suggesting that IGF2BP3 might be used as a potential prognostic biomarker for gliomas ( Liu et al, 2021b ; Sun et al, 2021 ; Xiong et al, 2022 ). The important role of modified m 6 A-related proteins in GBM provides new insights into the prognosis and treatment of GBM.…”