Objective The high toxicity of current therapies and frequent relapse in mature B-cell non-Hodgkin lymphomas (B-NHLs) reveal a substantial unmet clinical need for more effective targeted treatment strategies. To address this gap, Gene Set Enrichment Analysis (GSEA) of B-NHL datasets was conducted, uncovering marked enrichment of E2F transcription factors and their target genes. Despite the central role of E2F signaling in cell cycle control and oncogenesis, its contribution to pediatric B-NHLs has not been systematically characterized. Accordingly, we performed a comprehensive analysis of E2F signaling and its downstream targets to identify potential therapeutic and prognostic biomarkers in pediatric B-NHLs.
Methods The datasets used for this analysis were obtained from the Gene Expression Omnibus (GEO) database, and mRNA and protein expression levels were further validated via data from The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), and the Human Protein Atlas (HPA). Key bioinformatics findings were validated via quantitative PCR (qPCR) and cell proliferation assays. Survival analysis was conducted to evaluate the associations between gene expression levels and the prognosis of B-NHL patients. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and GSEA were employed to predict gene functions and associated pathways.
Results Childhood B-NHLs were markedly enriched for E2F gene set. The identified overlapping differentially expressed genes (DEGs) were linked to cell cycle regulation, DNA replication, and proliferative activity. E2F1 and hub genes such as POLD1, LIG1, MCM3, MCM6, and PCNA were markedly overexpressed in B-cell lymphoma. These genes demonstrated strong discriminatory potential as disease-associated signaling molecules. Moreover, the expression of POLD1 was closely associated with the proliferative capacity of B-NHLs.
Conclusion E2Fs and their downstream target genes are significantly overexpressed in pediatric B-NHLs, driving tumor cell proliferation. These molecules may serve as biomarkers for therapeutic stratification, prognosis, and disease monitoring in pediatric B-NHLs.
| [1] |
Bowzyk Al-Naeeb A, Ajithkumar T, Behan S, et al. Non-Hodgkin lymphoma. Bmj. 2018:k3204.
|
| [2] |
Cairo MS, Beishuizen A. Childhood, adolescent and young adult non-Hodgkin lymphoma: current perspectives. Br J Haematol., 2019, 185(6): 1021-1042
|
| [3] |
Ferry JA, Hill B, Hsi ED. Mature B, T and NK-cell, plasma cell and histiocytic/dendritic cell neoplasms: classification according to the World Health Organization and International Consensus Classification. J Hematol Oncol., 2024, 17(1): 51
|
| [4] |
Harker-Murray PD, Pommert L, Barth MJ. Novel therapies potentially available for pediatric B-cell non-Hodgkin lymphoma. J Natl Compr Canc Netw., 2020, 18(8): 1125-1134
|
| [5] |
Egan G, Goldman S, Alexander S. Mature B-NHL in children, adolescents and young adults: current therapeutic approach and emerging treatment strategies. Br J Haematol., 2019, 185(6): 1071-1085
|
| [6] |
Zöphel S, Küchler N, Jansky J, et al.. CD16+ as predictive marker for early relapse in aggressive B-NHL/DLBCL patients. Mol Cancer., 2024, 23(1): 210
|
| [7] |
Gao Y, Qiao X, Liu Z, et al.. The role of E2F2 in cancer progression and its value as a therapeutic target. Front Immunol., 2024, 15: 1397303
|
| [8] |
Kassab A, Gupta I, Moustafa AA. Role of E2F transcription factor in oral cancer: Recent insight and advancements. Semin Cancer Biol., 2023, 92: 28-41
|
| [9] |
Wang Y, Hu H, Liu H, et al.. Study of the role of E2F1 and TMEM132A in prostate cancer development. Front Biosci (Landmark Ed)., 2024, 29(10): 360
|
| [10] |
Liu N, Wang S, Li M, et al.. BET degrader exhibits lower antiproliferative activity than its inhibitor via EGR1 recruiting septins to promote E2F1-3 transcription in triple-negative breast cancer. Pharmacol Res., 2024, 208: 107377
|
| [11] |
Musiałek MW, Rybaczek D. Behavior of replication origins in Eukaryota–spatio-temporal dynamics of licensing and firing. Cell Cycle., 2015, 14(14): 2251-2264
|
| [12] |
Kim A, Benavente CA. Oncogenic roles of UHRF1 in cancer. Epigenomes., 2024, 8(3): 26
|
| [13] |
Teng Y, Liu R. E2F-mediated POLA2 upregulation is correlated with macrophage infiltration and poor prognosis in hepatocellular carcinoma. Transl Cancer Res., 2024, 13(4): 1848-1860
|
| [14] |
Guo Z, Zhao Y, Xu M, et al.. Natural killer cell-based signature: Prognostic analysis in head and neck squamous cell carcinoma. J Gene Med., 2024, 26(2): e3671
|
| [15] |
Wei J, Gao C, Lu C, et al.. The E2F family: a ray of dawn in cardiomyopathy. Mol Cell Biochem., 2025, 480(2): 825-839
|
| [16] |
Verdú-Bou M, Baptista MJ, Ribeiro ML, et al.. The role of miR-150-5p/E2F3/survivin axis in the pathogenesis of plasmablastic lymphoma and its therapeutic potential. Blood Adv., 2025, 9(12): 2953-2967
|
| [17] |
Spender LC, Inman GJ. TGF-beta induces growth arrest in Burkitt lymphoma cells via transcriptional repression of E2F–1. J Biol Chem., 2009, 284(3): 1435-1442
|
| [18] |
Xie B, Wang S, Jiang N, et al.. Cyclin B1/CDK1-regulated mitochondrial bioenergetics in cell cycle progression and tumor resistance. Cancer Lett., 2019, 443: 56-66
|
| [19] |
Petrova D, Cruz M, Sánchez MJ. BRCA1/2 testing for genetic susceptibility to cancer after 25 years: a scoping review and a primer on ethical implications. Breast., 2022, 61: 66-76
|
| [20] |
Moore XTR, Gheghiani L, Fu Z. The role of polo-like kinase 1 in regulating the forkhead box family transcription factors. Cells., 2023, 12(9): 1344
|
| [21] |
Borah NA, Reddy MM. Aurora kinase B inhibition: a potential therapeutic strategy for cancer. Molecules., 2021, 26(7): 1981
|
| [22] |
Jostes S, Vardabasso C, Dong J, et al. H2A.Z chaperones converge on E2F target genes for melanoma cell proliferation. Genes Dev. 2024;38(7–8):336–353.
|
| [23] |
Gao S, Song Q, Liu J, et al.. E2F1 mediates the downregulation of POLD1 in replicative senescence. Cell Mol Life Sci., 2019, 76(14): 2833-2850
|
| [24] |
Egelkrout EM, Robertson D, Hanley-Bowdoin L. Proliferating cell nuclear antigen transcription is repressed through an E2F consensus element and activated by geminivirus infection in mature leaves. Plant Cell., 2001, 13(6): 1437-1452
|
| [25] |
Ohtani K, Iwanaga R, Nakamura M, et al.. Cell growth-regulated expression of mammalian MCM5 and MCM6 genes mediated by the transcription factor E2F. Oncogene., 1999, 18(14): 2299-2309
|
| [26] |
Kent LN, Leone G. The broken cycle: E2F dysfunction in cancer. Nat Rev Cancer., 2019, 19(6): 326-338
|
| [27] |
Gola M, Stefaniak P, Godlewski J, et al.. Prospects of POLD1 in human cancers: a review. Cancers., 2023, 15(6): 1905
|
| [28] |
Zhang S, Zhou T, Wang Z, et al.. Post-translational modifications of PCNA in control of DNA synthesis and DNA damage tolerance-the implications in carcinogenesis. Int J Biol Sci., 2021, 17(14): 4047-4059
|
| [29] |
Sallmyr A, Bhandari SK, Naila T, et al.. Mammalian DNA ligases; roles in maintaining genome integrity. J Mol Biol., 2024, 436(1): 168276
|
| [30] |
Malysa A, Zhang XM, Bepler G. Minichromosome maintenance proteins: from DNA replication to the DNA damage response. Cells., 2024, 14(1): 12
|
| [31] |
Zhou Y, Nakajima R, Shirasawa M, et al.. Expanding roles of the E2F-RB-p53 pathway in tumor suppression. Biology., 2023, 12(12): 1511
|
Funding
Innovative Research Group Project of the National Natural Science Foundation of China(81874187)
RIGHTS & PERMISSIONS
The Author(s), under exclusive licence to the Huazhong University of Science and Technology
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