Mohammad Reza Naderi Allaf,1Hossein Javid,2,*Faeze Bakhshi,3Tahmineh Rahimi,4
1. Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran 2. Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran 3. Research Committee, Department of Medical Laboratory Science, Varastegan Institute for Medical Science, Mashhad, IRAN. 4. Research Committee, Department of Medical Laboratory Science, Varastegan Institute for Medical Science, Mashhad, IRAN.
Introduction: The majority of adults worldwide have been infected with the Epstein-Barr virus (EBV), a virus belonging to the gamma herpesvirus group. It can be regarded as the best-known oncovirus to some extent. EBV typically remains mostly inactive in persistent infection following initial infection, which usually occurs before adolescence. It has the potential to reactivate in specific circumstances, which could be linked to various cancers. Among human head and neck carcinomas (HNCs), nasopharyngeal carcinomas (NPCs) are distinguished by their consistent association with EBV, their unique geographic distribution, and their distinct histological features. NPC is currently the best-characterized human epithelial malignancy linked to EBV infection.
Methods: Scientific resources from PubMed, Science Direct, Springer, and Google Scholar were used to write this review study.
Results: Reports indicate that EBV infection is a significant risk factor and plays a crucial role in the development of NPC. Unlike its ability to transform primary B cells and render them immortal, EBV does not directly convert nasopharyngeal epithelial cells into proliferative clones. Instead, a hallmark of premalignant nasopharyngeal epithelial cells is latent EBV infection. Viral genes including Epstein–Barr virus–encoded small RNAs (EBERs) and Epstein–Barr virus nuclear antigen 1 (EBNA1), latent membrane protein 1 (LMP1), and latent membrane protein 2A (LMP2A) are expressed as a result of the latency program unique to epithelial cells. The changing state of premalignant nasopharyngeal epithelial cells is the first step toward the development of NPC. Through the deregulation of genes involved in DNA repair, cell cycle checkpoint, and anti-oncogenic activity, EBV causes genomic instability in infected premalignant cells. By preventing Chk1 activation, LMP1 causes a G2 checkpoint malfunction. This allows unrepaired chromatid breaks to progress through mitosis, which spreads and builds up over time, ultimately resulting in chromosomal instability. High expression of EBV-miR-BART suggests its role in promoting epithelial cell survival. by affecting gene expression and leading to inappropriate epigenetic modifications, EBV also plays a role in non-mutational genetic instability. EBV-encoded latent proteins and microRNAs can compromise host immune responses by interfering with cytokine signaling networks and antigen presentation. This interference encourages the infiltration of immune-regulating cells, which can stimulate metastasis and tumor growth. LMP1, an EBV-encoded protein, enhances the epithelial-mesenchymal transition (EMT) by regulating transcription factors such as Twist and Snail. Additionally, it boosts calreticulin production through the TGF-β pathway. In nasopharyngeal carcinoma (NPC), EBV induces angiogenesis by upregulating the expression of vascular cell adhesion molecule 1 (VCAM-1) with exosome-packaged EBERs. Furthermore, EBV regulates glucose metabolism in NPC by activating mTORC1 through LMP1, leading to NF-κB signaling and increased GLUT1 transcription. This process is mediated by the AKT/ERK/IKK signaling pathway.
Conclusion: Since EBV infection and NPC development are closely linked, EBV serology, which measures EBV DNA and antibodies against EBV oncoproteins, is a promising approach as a disease biomarker. It offers the potential to be used for minimal residual disease and therapeutic efficacy monitoring. Treatment options for NPCs differ according to stage. While radiation, chemotherapy, and surgery are standard treatments, surgical options are limited due to the deep placement of the tumor and the intricate anatomical features of the region where it is located. However, because NPC is a highly sensitive tumor to radiation and chemotherapy, the mainstay of care for patients with stage I/II NPC is either radiotherapy or chemotherapy, often administered alone or in combination. In the context of nasopharyngeal cancer, immunotherapy offers promising therapeutic potential. Key strategies in this area include immune checkpoint inhibitors, adoptive T-cell therapy, and EBV-directed immunization.