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Review
. 2021 Aug 3;13(15):3909.
doi: 10.3390/cancers13153909.

MicroRNA and Other Non-Coding RNAs in Epstein-Barr Virus-Associated Cancers

Kin Israel Notarte  1 , Suranga Senanayake  2 , Imee Macaranas  1 , Pia Marie Albano  3 , Lucia Mundo  4   5 , Eanna Fennell  5 , Lorenzo Leoncini  4 , Paul Murray  5   6   7
Affiliations
Review

MicroRNA and Other Non-Coding RNAs in Epstein-Barr Virus-Associated Cancers

Kin Israel Notarte et al. Cancers (Basel). .

Abstract

EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.

Keywords: Burkitt lymphoma; EBV; carcinogenesis; classical Hodgkin’s lymphoma; diffuse large B-cell lymphoma; gastric carcinoma; immune evasion; miRNA; microRNAome; nasopharyngeal carcinoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A model to explain the life cycle of EBV in B cells and the origin of EBV-positive B cell lymphomas. Trafficking B cells are presumed to become infected as they pass close to epithelium, potentially in the tonsils. The infected B cells probably then undergo proliferation driven by the Latency III virus gene expression program. The infected B cells enter a germinal center reaction in which only the EBNA1, LMP1, and LMP2A viral proteins are expressed (Latency II). LMP1 is a CD40 homologue and LMP2A is a B cell receptor (BCR)-mimic. Together LMP1 and LMP2A are thought to provide the signals necessary for the EBV-infected cells to survive a germinal center reaction and to differentiate into memory B cells and plasma cells. Plasma cells replicate the virus leading to the release of new virions, which can pass out into the oropharynx for infection of other susceptible hosts. Memory B cells provide the vehicle for long-term virus persistence and are characterized by an absence of virus protein expression (Latency 0). Memory B cells may switch on EBNA1 expression when they proliferate (Latency I). Distinct patterns of miRNA expression in ‘normal’ EBV-infected B cells are associated with Latency III and the other restricted forms of latency II/I/0 (listed in top right of figure). Latency I/0 is characterized by a strong expression of EBV BART4, 6-3p, 7 and a significantly higher expression of miR-17-5p compared to latency II showing modest level of EBV BART3*, 6-5p, and 8-5p. Latency III is characterized by intermediate level of EBV BART7*, 10, 11-3p, 13*, 14*, 15, 18-3p, and EBV-miR-BHRF1-2, 1-3, not expressed in the other forms of latency. The origin of the EBV-associated B cell lymphomas remains uncertain. Assumptions of origin are based largely on resemblance to normal B cell phenotypes and virus latency programs. BL tumors phenotypically resemble normal GC B cells and are probably derived from this stage of B cell differentiation. However, because BL usually expresses a Lat I phenotype, it has been suggested by others that BL could be derived from proliferating memory B cells. Figure made with Servier Medical Art. 2021. SMART—Servier Medical ART (online). Available online: https://smart.servier.com/, accessed on 5 July 2021.
Figure 2
Figure 2
Functions of selected EBV miRNAs in the pathogenesis of the different EBV-associated malignancies. Depicted are EBV-positive classical Hodgkin’s lymphoma showing EBV-LMP1 expression in HRS cells. Burkitt lymphoma showing the typical starry sky appearance on H&E. EBNA2 expression is shown in a Lat III-expressing diffuse large B cell lymphoma. EBNA1 expression is depicted in the two major EBV-associated epithelial neoplasms, nasopharyngeal carcinoma, and gastric carcinoma.
Figure 3
Figure 3
Potential clinical utility of EBV-encoded miRNAs. BART13-3p could aid in the detection of preclinical NPC, a cancer, which often presents late and when advanced, is associated with poor prognosis. In NKTL, which is characterized by early invasion and metastasis, miR-BART2-5p may have a role as diagnostic and predictive biomarker with the potential to identify those likely to respond to therapy. Identification of the risk of recurrence after potentially curative resection in patients with gastric cancer remains a priority; BART20-5p levels in EBVaGC might be useful in predicting recurrence free survival. Finally, rapidly emerging mRNA therapeutic technologies can be adopted to inhibit or mimic the action of miRNAs with oncogenic or tumor suppressive roles, respectively.
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