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Review
. 2023 Jun 14:13:1204030.
doi: 10.3389/fonc.2023.1204030. eCollection 2023.

The role of EBV-encoded miRNA in EBV-associated gastric cancer

Ting Liu  1 , Xiaoying Zhou  2 , Zhe Zhang  2   3 , Yutao Qin  1 , Rensheng Wang  1   2 , Yanning Qin  4 , Yuqi Huang  4 , Yingxi Mo  5 , Tingting Huang  1   2
Affiliations
Review

The role of EBV-encoded miRNA in EBV-associated gastric cancer

Ting Liu et al. Front Oncol. .

Abstract

Epstein-Barr virus (human herpesvirus 4, EBV) is a linear double-stranded DNA virus that infects over 90% of the population worldwide. However, our understanding of EBV's contribution to tumorigenesis of EBV-associated GC (EBVaGC) remains incomplete. Recent advancements in EBVaGC research have highlighted that EBV-encoded microRNAs (miRNAs) play prominent roles in critical cellular processes such as migration, cell cycle, apoptosis, cell proliferation, immune response, and autophagy. Notably, the largest group of EBV-encoded miRNAs, known as BamHI-A rightward transcripts (BARTs), exhibit bidirectional effects in EBVaGC. For instance, they present both anti-apoptotic and pro-apoptotic functions and enhance chemosensitivity while also conferring resistance to 5-fluorouracil. Despite these findings, the comprehensive mechanisms through which miRNAs contribute to EBVaGC are yet to be fully elucidated. In this work, we summarize the current evidence of the roles of miRNA in EBVaGC, particularly with the application of multi-omic techniques. Additionally, we discuss the application of miRNA in EBVaGC in retrospective analyses and provide novel perspectives on the use of miRNA in EBVaGC in translational medicine.

Keywords: Epstein-Barr virus; MicroRNAs; carcinogenesis; clinical application; gastric cancer.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Illustration of the transcription of Epstein-Barr virus (EBV) latent genes expressed in EBV-associated gastric cancer (EBVaGC). The latency genes expressed in EBVaGC include EBV-encoded small RNA (EBER)1, EBER2, EBV nuclear antigens1(EBNA1), and BART miRNAs. Most EBVaGC tumors lack or express low levels of latent membrane proteins (LMP) 1, LMP2A, and LMP2B. The BART region contains two subclusters: 1 and 2, with miR-BART2 located downstream of these two clusters.
Figure 2
Figure 2
Multifaceted roles of EBV-encoded miRNAs in modulating the cell biological functions in EBVaGC. After EBV infection, the synthesis of miRNA in normal gastric cells undergoes alterations. The process begins with the transcription of EBV DNA by RNA polymerase II (RNA pol II), generating primary miRNA (pri-miRNA). Subsequently, the pri-miRNA is cleaved by the enzyme Drosha in the cell nucleus, forming precursor miRNA (pre-miRNA). The pre-miRNA is then transported to the cytoplasm, where it undergoes further cleavage by Dicer-Transactivation Response RNA-Binding Protein (TRBP), producing mature miRNA. Once mature, the miRNA associates with the RNA-induced Silencing Complex (RISC) and binds to its target mRNA, exerting inhibitory or promoting effects. These EBV-encoded miRNAs play a significant role in the oncogenesis of gastric cancer, demonstrating both suppressive and promotive effects on critical cellular processes such as migration, cell proliferation, and apoptosis. Moreover, these miRNAs can modulate the cycles of both the host cell and the virus. Notably, EBV-encoded miRNAs profoundly impact immune responses through diverse mechanisms, including the regulation of PD-L1 expression. Additionally, miRNAs function to suppress autophagy, further contributing to their multifaceted role in EBV-associated gastric cancer.
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Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (U22A20322, to Z. Zhang), the National Natural Science Youth Foundation of China (82202939, to T. Huang), and China Postdoctoral Science Foundation (2022MD723765, to T. Huang).