In a groundbreaking study recently published in the distinguished journal Genes & Cancer, researchers have uncovered a novel molecular interaction between Epstein-Barr virus (EBV) and human papillomavirus (HPV) that may amplify the aggressiveness of cervical cancer. This research, led by Amir Hossein Alipour, Seyed Mohammad Ali Hashemi, and Jamal Sarvari from Shiraz University of Medical Sciences, sheds new light on the oncogenic role of EBV’s nuclear antigen 1 (EBNA1) in HPV-positive cervical cancer cells, revealing a complex viral synergy that could reshape current understanding of cervical carcinogenesis.
Cervical cancer remains one of the leading causes of cancer-related mortality among women worldwide. While infection with high-risk HPV types, particularly HPV-16 and HPV-18, is well-established as the principal etiological factor, emerging evidence suggests that other oncogenic viruses may collaborate to exacerbate disease progression. EBV, historically associated with malignancies like nasopharyngeal carcinoma and certain lymphomas, has increasingly been implicated in a variety of epithelial cancers, fueling speculation about its potential co-carcinogenic role in cervical cancer. This investigation provides compelling mechanistic insights into how EBV may influence gene expression within HPV-harboring cervical cancer cells.
Using the widely studied HeLa cell line, which naturally contains HPV-18 DNA integrated into the genome, the team transfected cells with a plasmid encoding EBV’s EBNA1 protein to mimic co-infection scenarios. Through meticulous real-time quantitative PCR analyses, they examined differential expression of four key genes—Derlin1, PSMD10, ZEB1, and CNN3—that play variable roles in cellular processes such as protein degradation pathways, epithelial-mesenchymal transition, and cytoskeletal regulation. Strikingly, EBNA1 prompted a pronounced upregulation of Derlin1 and PSMD10 mRNA levels, with Derlin1 expression escalating threefold and PSMD10 doubling relative to control cells.
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Derlin1 is intimately involved in the endoplasmic reticulum-associated degradation (ERAD) pathway, a critical cellular quality control mechanism responsible for identifying and targeting misfolded proteins for proteasomal degradation. Its overexpression has been correlated with resistance to chemotherapeutic agents and enhanced survival of malignant cells. PSMD10, also known as gankyrin, is a regulatory subunit of the 26S proteasome implicated in oncogenic pathways including p53 degradation and retinoblastoma protein inactivation. Overexpression of PSMD10 has been linked to accelerated tumor growth and poor prognosis in various malignancies, including hepatocellular carcinoma and pancreatic cancer.
The observed upregulation of these two genes upon EBNA1 expression suggests that EBV may potentiate tumorigenic processes within cervical epithelial cells by enhancing proteasome-mediated degradation of tumor suppressor proteins and promoting cellular adaptations that favor malignancy. Conversely, the expression levels of ZEB1, a transcription factor involved in epithelial-mesenchymal transition and metastasis, and CNN3, a cytoskeletal protein, were not significantly altered. This selective gene modulation emphasizes the specificity by which EBNA1 may manipulate cellular pathways in the context of HPV-associated oncogenesis.
Statistical analyses underscored the significance of these findings, with p-values of 0.028 supporting the notion that EBNA1-induced transcriptional upregulation of Derlin1 and PSMD10 was not due to chance. These results mark a pivotal step in understanding how EBV can modulate the tumor microenvironment and gene expression landscape in cervical cancer cells already compromised by HPV infection. Moreover, this molecular crosstalk might contribute to enhanced cancer cell survival, proliferation, and potentially treatment resistance, compounding the clinical challenges in managing cervical carcinoma.
The study’s implications are manifold. Firstly, it reinforces the hypothesis that viral co-infections may create synergistic oncogenic milieus, complicating the pathogenesis beyond the effects of HPV alone. Secondly, by identifying Derlin1 and PSMD10 as downstream effectors of EBNA1 in cervical cancer cells, the research opens avenues for targeted therapeutic interventions. Modulating these pathways could attenuate the aggressive phenotypes observed in EBV/HPV co-infected tumors, potentially improving patient outcomes.
However, the authors caution that these findings are preliminary and derived largely from in vitro systems. Further in vivo investigations utilizing animal models and patient-derived specimens are essential to validate the clinical relevance of EBNA1’s regulatory effects on Derlin1 and PSMD10 expression. Protein-level analyses and functional assays to determine how modulating these gene products influences tumor growth, apoptotic resistance, and metastatic potential will be crucial subsequent steps.
Interestingly, the study also supports a broader understanding of how viruses hijack host cellular machinery to enhance their survival and propagation while inadvertently or deliberately facilitating oncogenesis. EBNA1, known primarily for its role in EBV genome maintenance, emerges here as a potent modulator of host gene expression with significant pathological consequences in the backdrop of HPV-mediated transformation.
This discovery further emphasizes the necessity for comprehensive viral screening in cervical cancer diagnostics, especially in populations with high prevalence of EBV and HPV co-infection. Understanding the interplay between these viruses can inform risk stratification, prognosis, and personalized therapeutic strategies.
In conclusion, this research represents a significant advancement in unraveling the molecular complexity of cervical cancer. By uncovering the capacity of EBV’s EBNA1 to selectively upregulate genes associated with cancer cell survival and proteasomal activity in HPV-positive cervical cancer cells, it introduces a new paradigm for viral co-factors in oncogenesis. As cervical cancer remains a major global health burden, such insights are invaluable for developing multifaceted interventions that address the viral dimensions of this malignancy.
Ongoing research building on these findings holds promise not only for clarifying the biological underpinnings of virus-associated cancers but also for propelling the development of innovative therapeutics aimed at viral proteins or their downstream targets. The intricate dance between EBV and HPV within cervical cells is a stark reminder of the complexities inherent in cancer biology, urging the scientific community to embrace integrative approaches that consider viral co-infections as critical components of oncogenic pathways.
Subject of Research: Cells
Article Title: Epstein-Barr virus nuclear antigen 1 upregulates Derlin1 and PSMD10 expression in HeLa cells
News Publication Date: August 6, 2025
Web References:
Genes & Cancer Journal
DOI: 10.18632/genesandcancer.242
Image Credits: Copyright: © 2025 Alipour et al. Licensed under Creative Commons Attribution License (CC BY 4.0).
Keywords: cancer, cervical carcinoma, Epstein–Barr virus, EBNA1, HPV co-infection, Derlin1, PSMD10, proteasome, viral oncogenesis, cervical cancer, HeLa cells
Tags: cancer-related mortality in womencervical cancer researchcervical carcinogenesis insightsEBNA1 role in cancerEpstein-Barr virus interactionsHeLa cell line studieshigh-risk HPV typesHPV and EBV synergymolecular interactions in canceroncogene activation mechanismsoncogenic viruses in cancerviral co-carcinogenesis
