AccScience Publishing / EJMO / Online First / DOI: 10.36922/EJMO026090101
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ORIGINAL RESEARCH ARTICLE

Integrated identification, functional characterization, and clinical significance of key genes during cervical cancer progression

Shengyi Gu1 Meiqin Yang1*
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1 Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, School of Life Science and Technology, Tongji University, Shanghai, China
Received: 26 February 2026 | Revised: 12 June 2026 | Accepted: 1 July 2026 | Published online: 13 July 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Abstract

Introduction: Cervical cancer evolves from normal cervical epithelium through a multifaceted pathway, first to high-grade squamous intraepithelial lesions (HSILs) and subsequently culminating in invasive cancer, yet the specific molecular mechanisms driving this progression remain poorly understood.

Objective: To identify genes persistently dysregulated during cervical lesion progression and to evaluate their clinical relevance with respect to prognosis, immune infiltration, and therapeutic response.

Methods: Two independent gene expression datasets (GSE7803 and GSE64217) were analyzed to screen persistently differentially expressed genes (DEGs) across normal cervix, HSIL, and cervical cancer. Public databases and clinical samples were used to validate the hub genes initially identified through functional enrichment and protein–protein interaction analyses. Associations with patient survival, immune infiltration, and drug sensitivity were further analyzed using integrated bioinformatics platforms.

Results: Eighteen common persistent DEGs were identified, primarily enriched in cell cycle regulation and epithelial differentiation. Four hub genes (AURKA, ECT2, RFC4, and PCNA) showed progressive upregulation as cervical lesions progressed and were associated with clinicopathological features. Elevated RFC4 and PCNA levels were significantly associated with improved survival. Immune analysis revealed distinct correlation patterns for RFC4 and PCNA expression: positive with B cells and effector memory immune cells, and negative with regulatory T cells. Drug sensitivity analysis showed that elevated RFC4 and PCNA expression were associated with lower IC50 values, whereas AURKA and ECT2 were linked to potential drug resistance.

Conclusion: AURKA, ECT2, RFC4, and PCNA are key regulators of cervical lesion progression, among which RFC4 and PCNA are promising prognostic biomarkers and potential therapeutic targets.

Keywords
Cervical cancer
High-grade squamous intraepithelial lesions
Bioinformatics analysis
Hub genes
Immune infiltration
Funding
This study was supported by a grant from the National Science Foundation of China (No. 82403164).
Conflict of interest
The authors have no conflicts of interest.
References
  1. Perkins RB, Wentzensen N, Guido RS, Schiffman M. Cervical Cancer Screening: A Review. JAMA. 2023;330(6):547-558. doi: 10.1001/jama.2023.13174

 

  1. Xu M, Cao C, Wu P, Huang X, Ma D. Advances in cervical cancer: current insights and future directions. Cancer Commun (Lond). 2025;45(2):77-109. doi: 10.1002/cac2.12629

 

  1. Perkins RB, Wolf AMD, Church TR, et al. Self-collected vaginal specimens for human papillomavirus testing and guidance on screening exit: An update to the American Cancer Society cervical cancer screening guideline. CA Cancer J Clin. 2026;76(1):e70041. doi: 10.3322/caac.70041

 

  1. Molina MA, Steenbergen RDM, Pumpe A, Kenyon AN, Melchers WJG. HPV integration and cervical cancer: a failed evolutionary viral trait. Trends Mol Med. 2024;30(9):890- 902. doi: 10.1016/j.molmed.2024.05.009

 

  1. Arroyo Mühr LS, Gini A, Yilmaz E, et al. Concomitant human papillomavirus (HPV) vaccination and screening for elimination of HPV and cervical cancer. Nat Commun. 2024;15(1):3679. doi: 10.1038/s41467-024-47909-x

 

  1. Wei F, Georges D, Man I, Baussano I, Clifford GM. Causal attribution of human papillomavirus genotypes to invasive cervical cancer worldwide: a systematic analysis of the global literature. Lancet. 2024;404(10451):435-444. doi: 10.1016/s0140-6736(24)01097-3

 

  1. Matthews HK, Bertoli C, de Bruin RAM. Cell cycle control in cancer. Nat Rev Mol Cell Biol. 2022;23(1):74-88. doi: 10.1038/s41580-021-00404-3

 

  1. Saxena S, Zou L. Hallmarks of DNA replication stress. Mol Cell. 2022;82(12):2298-2314. doi: 10.1016/j.molcel.2022.05.004

 

  1. Malagón T, Franco EL, Tejada R, Vaccarella S. Epidemiology of HPV-associated cancers past, present and future: towards prevention and elimination. Nat Rev Clin Oncol. 2024;21(7):522-538. doi: 10.1038/s41571-024-00904-z

 

  1. Mayadev J, Vázquez Limón JC, Ramírez Godinez FJ, et al. Ultrasensitive detection and tracking of circulating tumor DNA to predict relapse and survival in patients with locally advanced cervical cancer: phase III CALLA trial analyses. Ann Oncol. 2025;36(9):1047-1057. doi: 10.1016/j.annonc.2025.05.533

 

  1. Rahangdale L, Mungo C, O’Connor S, Chibwesha CJ, Brewer NT. Human papillomavirus vaccination and cervical cancer risk. BMJ. 2022;379:e070115. doi: 10.1136/bmj-2022-070115

 

  1. Griffioen MS, Runello F, Steenbergen RDM. DNA Methylation in Cervical Intraepithelial Neoplasia and Cervical Cancer: Triage and Management. Curr Top Microbiol Immunol. 2026;448:93-112. doi: 10.1007/978-3-032-17775-9_5

 

  1. Volkova LV, Pashov AI, Omelchuk NN. Cervical Carcinoma: Oncobiology and Biomarkers. Int J Mol Sci. 2021;22(22):12571. doi: 10.3390/ijms222212571

 

  1. Monk BJ, Enomoto T, Kast WM, et al. Integration of immunotherapy into treatment of cervical cancer: Recent data and ongoing trials. Cancer Treat Rev. 2022;106:102385. doi: 10.1016/j.ctrv.2022.102385

 

  1. Castle PE, Einstein MH, Sahasrabuddhe VV. Cervical cancer prevention and control in women living with human immunodeficiency virus. CA Cancer J Clin. 2021;71(6):505- 526. doi: 10.3322/caac.21696

 

  1. Ahmed SMQ, Sasikumar J, Laha S, Das SP. Multifaceted role of the DNA replication protein MCM10 in maintaining genome stability and its implication in human diseases. Cancer Metastasis Rev. 2024;43(4):1353-1371. doi: 10.1007/s10555-024-10209-3

 

  1. Pu C, Xing B, Wang S, Liu Z, Zhao Y. Advancements in single-cell sequencing for cervical cancer research. Mol Cell Biochem. 2025;481(2):615-637. doi: 10.1007/s11010-025-05407-8

 

  1. Wang S, Liu C, Ye D, et al. Deciphering the mechanism of baicalein in cervical cancer via bioinformatics, machine learning and computational simulations: PIM1 and CDK2 are key target proteins. Int J Biol Macromol. 2025;311(Pt 3):144014. doi: 10.1016/j.ijbiomac.2025.144014

 

  1. Voelker RA. Cervical Cancer Screening. JAMA. 2023;330(20):2030. doi: 10.1001/jama.2023.21987

 

  1. Zhao S, Huang L, Basu P, et al. Cervical cancer burden, status of implementation and challenges of cervical cancer screening in Association of Southeast Asian Nations (ASEAN) countries. Cancer Lett. 2022;525:22-32. doi: 10.1016/j.canlet.2021.10.036

 

  1. Cao G, Yue J, Ruan Y, et al. Single-cell dissection of cervical cancer reveals key subsets of the tumor immune microenvironment. EMBO J. 2023;42(16):e110757. doi: 10.15252/embj.2022110757

 

  1. Falcaro M, Castañon A, Ndlela B, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet. 2021;398(10316):2084-2092. doi: 10.1016/s0140-6736(21)02178-4

 

  1. Glaviano A, Singh SK, Lee EHC, et al. Cell cycle dysregulation in cancer. Pharmacol Rev. 2025;77(2):100030. doi: 10.1016/j.pharmr.2024.100030

 

  1. Kanehisa M, Furumichi M, Sato Y, Kawashima M, Ishiguro- Watanabe M. KEGG for taxonomy-based analysis of pathways and genomes. Nucleic Acids Res. 2023;51(D1):D587-D592. doi: 10.1093/nar/gkac963

 

  1. Li X, You Q. Sanguinarine identified as a natural dual inhibitor of AURKA and CDK2 through network pharmacology and bioinformatics approaches. Sci Rep. 2024;14(1):29608. doi: 10.1038/s41598-024-81063-0

 

  1. Vats P, Saini C, Baweja B, et al. Aurora kinases signaling in cancer: from molecular perception to targeted therapies. Mol Cancer. 2025;24(1):180. doi: 10.1186/s12943-025-02353-3

 

  1. Nikhil K, Shah K. The significant others of aurora kinase a in cancer: combination is the key. Biomark Res. 2024;12(1):109. doi: 10.1186/s40364-024-00651-4

 

  1. Deng B, Ke B, Tian Q, Gao Y, Zhai Q, Zhang W. Targeting AURKA with multifunctional nanoparticles in CRPC therapy. J Nanobiotechnology. 2024;22(1):803. doi: 10.1186/s12951-024-03070-7

 

  1. Oladipo KH, Parish JL. De-regulation of aurora kinases by oncogenic HPV; implications in cancer development and treatment. Tumour Virus Res. 2025;19:200314. doi: 10.1016/j.tvr.2025.200314

 

  1. Liu X, Zhang J, Ju S, et al. ECT2 promotes malignant phenotypes through the activation of the AKT/mTOR pathway and cisplatin resistance in cervical cancer. Cancer Gene Ther. 2023;30(1):62-73. doi: 10.1038/s41417-022-00525-7

 

  1. Huang S, Wei X, Wang Y, et al. Single-cell analysis reveals the regulatory role of ECT2 in HPV-driven cervical carcinogenesis process. Infect Agent Cancer. 2025;20(1):66. doi: 10.1186/s13027-025-00696-6

 

  1. Cook DR, Kang M, Martin TD, et al. Aberrant Expression and Subcellular Localization of ECT2 Drives Colorectal Cancer Progression and Growth. Cancer Res. 2022;82(1):90- 104. doi: 10.1158/0008-5472.CAN-20-4218

 

  1. Tran AT, Wisniewski EO, Mistriotis P, et al. Cytoplasmic anillin and Ect2 promote RhoA/myosin II-dependent confined migration and invasion. Nat Mater. 2025;24(9):1476-1488. doi: 10.1038/s41563-025-02269-9

 

  1. Sheng L, Liang M, Wang Y, et al. Research progress of ECT2 and RhoA-related signaling pathways in gynecological tumors. Front Cell Dev Biol. 2025;13:1602649. doi: 10.3389/fcell.2025.1602649

 

  1. Salta S, Lobo J, Magalhães B, Henrique R, Jerónimo C. DNA methylation as a triage marker for colposcopy referral in HPV-based cervical cancer screening: a systematic review and meta-analysis. Clin Epigenetics. 2023;15(1):125. doi: 10.1186/s13148-023-01537-2

 

  1. Abbasi W, French CE, Rockowitz S, Kenna MA, Eliot Shearer A. Evaluation of copy number variants for genetic hearing loss: a review of current approaches and recent findings. Hum Genet. 2022;141(3-4):387-400. doi: 10.1007/s00439-021-02365-1

 

  1. Zhang J, Meng S, Wang X, et al. Sequential gene expression analysis of cervical malignant transformation identifies RFC4 as a novel diagnostic and prognostic biomarker. BMC Med. 2022;20(1):437. doi: 10.1186/s12916-022-02630-8

 

  1. Mao M, Ji H, Yu WQ, et al. RFC4 drives temozolomide resistance in glioblastoma by activating STK38-BECN1- dependent autophagy. Nat Commun. 2026;17(1):4348. doi: 10.1038/s41467-026-70798-1

 

  1. Slebos RJ, Yi Y, Ely K, et al. Gene expression differences associated with human papillomavirus status in head and neck squamous cell carcinoma. Clin Cancer Res. 2006;12(3 Pt 1):701-709. doi: 10.1158/1078-0432.CCR-05-2017

 

  1. Chua GNL, Beckwitt EC, Miller-Browne V, et al. A non-catalytic role for RFC in PCNA-mediated processive DNA synthesis. Cell. 2026;189(4):1124-1134.e14. doi: 10.1016/j.cell.2025.12.029

 

  1. Wang S, Li J, Chen Y, et al. Oridonin derivative DLC13 targeting proliferating cell nuclear antigen to overcome oxaliplatin resistance in colorectal cancer. Drug Resist Updat. 2026;86:101390. doi: 10.1016/j.drup.2026.101390

 

  1. Zhang T, Rawal Y, Jiang H, Kwon Y, Sung P, Greenberg RA. Break-induced replication orchestrates resection-dependent template switching. Nature. 2023;619(7968):201-208. doi: 10.1038/s41586-023-06177-3

 

  1. Lai Z, Zhang Y, Huang W, et al. Brusatol ameliorates irinotecan-induced delayed diarrhea via inhibition of the cGAS-STING pathway and modulation of intestinal flora. Phytomedicine. 2025;145:157071. doi: 10.1016/j.phymed.2025.157071

 

  1. Huang B, Zheng J, Chen B, Wu M, Xiao L. Analysis of the correlation between RFC4 expression and tumor immune microenvironment and prognosis in patients with cervical cancer. Front Genet. 2025;16:1514383. doi: 10.3389/fgene.2025.1514383

 

  1. Ferrall L, Lin KY, Roden RBS, Hung CF, Wu TC. Cervical Cancer Immunotherapy: Facts and Hopes. Clin Cancer Res. 2021;27(18):4953-4973. doi: 10.1158/1078-0432.CCR-20-2833

 

  1. Mukherjee A, Manna S, Singh A, Ray A, Srivastava S. Investigating Cisplatin Resistance in Squamous Cervical Cancer: Proteomic Insights into DNA Repair Pathways and Omics-Based Drug Repurposing. J Proteome Res. 2025;24(6):2628-2642. doi: 10.1021/acs.jproteome.4c00885

 

  1. Dai D, Pei Y, Zhu B, et al. Chemoradiotherapy-induced ACKR2(+) tumor cells drive CD8(+) T cell senescence and cervical cancer recurrence. Cell Rep Med. 2024;5(5):101550. doi: 10.1016/j.xcrm.2024.101550

 

  1. Zhang H, Wang X, Ma Y, et al. Review of possible mechanisms of radiotherapy resistance in cervical cancer. Front Oncol. 2023;13:1164985. doi: 10.3389/fonc.2023.1164985
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Eurasian Journal of Medicine and Oncology, Electronic ISSN: 2587-196X Print ISSN: 2587-2400, Published by AccScience Publishing