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Roles of Inflammasomes in Epstein-Barr Virus-Associated Nasopharyngeal Cancer.

ABSTRACT: Epstein-Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host's antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC.

SUBMITTER: Looi CK

PROVIDER: S-EPMC8069343 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Microbiota has recently emerged as a critical factor associated with multiple malignancies. Nasopharyngeal carcinoma (NPC) is highly associated with Epstein-Barr virus (EBV); the oncovirus resides and is transmitted in the oral cavity. However, the alternation of oral microbiota in NPC patients and its potential link to EBV reactivation and host cell response under the simultaneous existence of EBV and specific bacteria is largely unknown. Here, oral microbiota profiles of 303 NPC patients and controls with detailed clinical information, including serum EBV anti-virus capsid antigen (VCA) IgA level, were conducted. A distinct microbial community with lower diversity and imbalanced composition in NPC patients was observed. Notably, among enriched bacteria in patients, Streptococcus sanguinis was associated with anti-VCA IgA, an indicator of NPC risk and EBV reactivation. By measuring the concentration of its metabolite, hydrogen peroxide (H2O2), in the saliva of clinical patients, we found the detection rate of H2O2 was 2-fold increased compared to healthy controls. Further coculture assay of EBV-positive Akata cells with bacteria in vitro showed that S. sanguinis induced EBV lytic activation by its metabolite, H2O2. Host and EBV whole genome-wide transcriptome sequencing and EBV methylation assays showed that H2O2 triggered the host cell signaling pathways, notably tumor necrosis factor alpha (TNF-α) via NF-κB, and induced the demethylation of the global EBV genome and the expression of EBV lytic-associated genes, which could result in an increase of virus particle release and potential favorable events toward tumorigenesis. In brief, our study identified a characterized oral microbial profile in NPC patients and established a robust link between specific oral microbial alteration and switch of latency to lytic EBV infection status in the oral cavity, which provides novel insights into EBV's productive cycle and might help to further clarify the etiology of NPC. IMPORTANCE EBV is classified as the group I human carcinogen and is associated with multiple cancers, including NPC. The interplays between the microbiota and oncovirus in cancer development remain largely unknown. In this study, we investigate the interactions between resident microbes and EBV coexistence in the oral cavity of NPC patients. We identify a distinct oral microbial feature for NPC patients. Among NPC-enriched bacteria, we illustrated that a specific species, S. sanguinis, associated with elevated anti-IgA VCA in patients, induced EBV lytic activation by its by-product, H2O2, and activated the TNF-α/NF-κB pathway of EBV-positive B cells in vitro, together with increased detection rate of H2O2 in patients' oral cavities, which strengthened the evidence of bacteria-virus-host interaction in physiological circumstances. The effects of imbalanced microbiota on the EBV latent-to-lytic switch in the oral cavity might create the likelihood of EBV infection in epithelial cells at the nasopharynx and help malignant transition and cancer development.

Project description:Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) infection in regions in which it is endemic, including Southern China and Southeast Asia. The high mortality rates of NPC patients with advanced and recurrent disease highlight the urgent need for effective treatments. While recent genomic studies have revealed few druggable targets, the unique interaction between the EBV infection and host cells in NPC strongly implies that targeting EBV may be an efficient approach to cure this virus-associated cancer. Key features of EBV-associated NPC are the persistence of an episomal EBV genome and the requirement for multiple viral latent gene products to enable malignant transformation. Many translational studies have been conducted to exploit these unique features to develop pharmaceutical agents and therapeutic strategies that target EBV latent proteins and induce lytic reactivation in NPC. In particular, inhibitors of the EBV latent protein EBNA1 have been intensively explored, because of this protein's essential roles in maintaining EBV latency and viral genome replication in NPC cells. In addition, recent advances in chemical bioengineering are driving the development of therapeutic agents targeting the critical functional regions of EBNA1. Promising therapeutic effects of the resulting EBNA1-specific inhibitors have been shown in EBV-positive NPC tumors. The efficacy of multiple classes of EBV lytic inducers for NPC cytolytic therapy has also been long investigated. However, the lytic-induction efficiency of these compounds varies among different EBV-positive NPC models in a cell-context-dependent manner. In each tumor, NPC cells can evolve and acquire somatic changes to maintain EBV latency during cancer progression. Unfortunately, the poor understanding of the cellular mechanisms regulating EBV latency-to-lytic switching in NPC cells limits the clinical application of EBV cytolytic treatment. In this review, we discuss the potential approaches for improvement of the above-mentioned EBV-targeting strategies.

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Roles of Inflammasomes in Epstein-Barr Virus-Associated Nasopharyngeal Cancer.

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