EBNA1BP2 identified as potential prognostic biomarker for multiple tumor types in pan-cancer analysis

Abstract

Background: Epstein-Barr virus (EBV) infection has been closely linked to the development of various types of cancer. EB nuclear antigen 1 binding protein 2 (EBNA1BP2) is a crucial molecule for stable isolation of EBV in latent infection. However, the role of EBNA1BP2 in multiple tumor types is remains unclear. In this study, we comprehensively analyzed the functional characteristics of EBNA1BP2 and investigate its potential as a prognostic biomarker in pan-cancer.

Methods: We utilized data from TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) databases and employed various bioinformatics analysis tools, including TIMER2.0, HPA, GEPIA2.0, PrognoScan, cBioPortal, CancerSEA, and BioGRID to explore the expression pattern, prognostic value, immune infiltration, and methylation level of EBNA1BP2 in pan-cancer. Additionally, we conducted enrichment analysis of genes associated with EBNA1BP2 to identify potential biological functions and pathways.

Results: Our analysis revealed that EBNA1BP2 expression was significantly higher in tumor tissues compared to tumor-adjacent tissues. We observed that lower expression of EBNA1BP2 in adrenocortical carcinoma (ACC), brain lower grade glioma (LGG), sarcoma (SARC), and uterine carcinosarcoma (UCS) was significantly associated with improved overall survival (OS) and disease-free survival (DFS). Furthermore, the promoter methylation level of EBNA1BP2 was downregulated in the majority of cancer types. At the single-cell level, EBNA1BP2 was found to be positively correlated with cell cycle and DNA repair processes, while negatively correlated with hypoxia. Additionally, EBNA1BP2 was associated with the infiltration of immune cells such as B cells, cancer-associated fibroblast cells, and CD8+ T cells. Gene enrichment analysis indicated that EBNA1BP2 was mainly involved in nucleoplasm and RNA binding pathways.

Conclusion: Our findings suggest that EBNA1BP2 may serve as a potential prognostic biomarker for survival in pan-cancer. Further experimental studies are needed to validate these findings and explore the underlying mechanisms by which EBNA1BP2 contributes to tumorigenesis.

Keywords: Biomarker; EBNA1BP2; Pan-cancer; Prognosis.

Fig. 1

Expression and protein levels of EBNA1BP2 in pan-cancer. A Expression level of EBNA1BP2 in human tumors from TIMER2.0. B Box plot representation the expression level of EBNA1BP2 in DLBC, LAML, OV and THYM from GTEx and TCGA database. C Total protein level of EBNA1BP2 in BRCA, OV, COAD, KIRC, LUAD, HNSC, PAAD, GBM and LIHC were analyzed using CPTAC. D GEPIA2.0 was used to compare EBNA1BP2 expression levels in different pathological stages of KICH, KIRC and LIHC. *p < 0.05; **p < 0.01; ***p < 0.001. EBNA1BP2: EB nuclear antigen 1 binding protein 2; GTEx: Genotype-Tissue Expression; TCGA: The Cancer Genome Atlas; CPTAC: Clinical Proteomic Tumor Analysis Consortium; DLBC: lymphoid neoplasm diffuse large B-cell lymphoma; LAML: acute myeloid leukemia; OV: ovarian serous cystadenocarcinoma; THYM: thymoma; BRCA: breast invasive carcinoma; COAD: colon adenocarcinoma; KIRC, kidney renal clear cell carcinoma; LUAD: lung adenocarcinoma; HNSC: head and neck squamous cell carcinoma; PAAD: pancreatic cancer; GBM: polymorphous glioblastoma; LIHC, liver hepatocellular carcinoma; KICH, kidney chromophobe

Fig. 2

Comparison of EBNA1BP2 expression in normal tissue and tumor tissue. A–C The expression level of EBNA1BP2 obtained by UALCAN and the corresponding immunohistochemical images obtained by HAP platform both showed up-regulated expression of EBNA1BP2 in breast, liver and lung derived tumor tissues. UALCAN: The University of ALabama at Birmingham CANcer data analysis Portal; HPA: Human Protein Atlas

Fig. 3

The relationship between the expression level of EBNA1BP2 and prognosis of pan-cancer. A, B Survival charts and Kaplan–Meier curves show the relationship between the expression level of EBNA1BP2 and OS (A) and DFS (B) in human tumors were obtained by GEPIA2.0. OS: overall survival; DFS: disease-free survival; GEPIA2.0: Gene Expression Profiling Interactive Analysis, version 2

Fig. 4

EBNA1BP2 gene mutation in different cancers. The altered frequencies of different mutation types (A) and mutation sites (B) in pan-cancer were shown using cBioPortal. C The 3D protein structure of EBNA1BP2 was shown. cBioPortal, The cBio Cancer Genomics Portal

Fig. 5

Comparison of differences in promoter methylation levels of EBNA1BP2 in cancer. EBNA1BP2 methylation values of normal tissues and primary tumor tissues were analyzed by UALCAN tool

Fig. 6

The correlation between EBNA1BP2 expression level and immune cells in tumors. A–C TIMER2.0 database was used to analyze the relationship between EBNA1BP2 expression and immune infiltration of B cells (A), cancer-associated fibroblasts (B) and T cells CD8+ (C). TIMER, EPIC, TIDE, QUANTISEQ, CIBERSORT, CIBERSORT-ABS, XCELL, MCPCOUNTER and other algorithms are used for analysis. Red for positive correlation (0–1) and blue negative correlation (− 1 to 0). A correlation of p < 0.05 was considered statistically significant. A cross indicates that the correlation is not significant. TIMER2.0: Tumor Immune Estimation Resource, version 2

Fig. 7

EBNA1BP2 gene expression at the single-cell level. A, B Using CancerSEA tools analysis EBNA1BP2 expression and tumor in the relationship between different functional status. C The single-cell expression profile of EBNA1BP2 in RB, UM and LUAD was shown by T-SNE plot. *p < 0.05; **p < 0.01; ***p < 0.001. RB: retinoblastoma; UM: uveal melanoma; LUAD: lung adenocarcinoma

Fig. 8

Functional enrichment and pathway analysis of EBNA1BP2-related genes. A EBNA1BP2 related gene is available by the BioGRID website and 11 proteins have been shown. B The top six genes most related to EBNA1BP2 were obtained using GEPIA2.0, which were PPIH, DPH2, YBX1, MRTO4, MED8 and CDC20. p-value < 0.001. C Heat map results confirmed EBNA1BP2 gene expression and six (PPIH DPH2, YBX1, MRTO4, MED8 and CDC20) in pan-carcinoma were positively correlated. D GO and KEGG enrichment analysis of EBNA1BP2-related genes. BioGRID: Biological General Repository for Interaction Datasets; PPIH: Homo sapiens peptidylprolyl isomerase H; DPH2: diphthamide biosynthesis 2; YBX1: Homo sapiens Y-box in most cancers binding protein 1; MRTO4: Homo sapiens MRT4 homolog, ribosome maturation factor; MED8: Homo sapiens mediator complex subunit 8; CDC20: Homo sapiens cell division cycle 20; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes