Long Noncoding Rnas Involvement in Epstein-Barr Virus Infection And
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Zhang et al. Virology Journal (2020) 17:51 https://doi.org/10.1186/s12985-020-01308-y REVIEW Open Access Long noncoding RNAs involvement in Epstein-Barr virus infection and tumorigenesis Jing Zhang1,2,3, Xiaohan Li1,2,3, Jingjin Hu1,2,3, Pengfei Cao2, Qijia Yan1,2, Siwei Zhang1,2,3, Wei Dang1,2,3 and Jianhong Lu1,2* Abstract The Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus related to various types of cancers, including epithelial nasopharyngeal carcinoma, gastric carcinoma, and lymphoma. Long noncoding RNAs (lncRNAs) are expressed extensively in mammalian cells and play crucial roles in regulating various cellular processes and multiple cancers. Cellular lncRNAs can be differentially expressed induced by EBV infection. The dysregulated lncRNAs probably modulate the host immune response and other biological functions. At present, lncRNAs have been found to be significantly increased or decreased in EBV-infected cells, exosomes and EBV-associated cancers, suggesting their potential function and clinical application as biomarkers. In addition, EBV-encoded lncRNAs, BART and BHLF1 lncRNAs, may play roles in the viral oncogenesis. Analysis of the specific lncRNAs involved in interactions with the EBV machinery will provide information on their potential mechanism of action during multiple steps of EBV tumorigenesis. Here, we review the current knowledge regarding EBV- related lncRNAs and their possible roles in the pathogenesis of EBV-associated cancers. Keywords: Long noncoding RNA, Epstein-Barr virus, Tumorigenesis, Epithelial cancer, Lymphoma Background lymphoma, nasopharyngeal carcinoma (NPC), gastric can- Epstein-Barr virus (EBV) is a ubiquitous γ-herpesvirus, cer (GC), Hodgkin’s disease and breast cancer [1, 2]. which is the first confirmed human tumor virus [1]. EBV is In human genomes, fewer than 2% of genes are tran- able to establish latent infection in B lymphocytes and scribed into mRNAs [3]. Emerging evidence has shown other types of cells such as T, NK, and some epithelial cells. that many noncoding RNAs (ncRNAs) also play import- Primary EBV infection typically appears in childhood as a ant cellular functions. Long noncoding RNAs (lncRNAs) symptomless or mild infection. The establishment of viral are defined as RNAs over 200 nucleotides in length latency is vital to maintain lifelong persistence of the virus without protein-coding ability and have essential func- inside the infected cells. In the latent status, EBV exhibits a tions for a range of biological processes [4]. LncRNAs severely restricted gene expression profile for the purpose are mainly the transcribed and spliced products of RNA of avoiding host immune surveillance [1, 2]. EBV infection polymerase II transcription. They are usually 5′ capped is associated with multiple diseases such as Burkett’s and may contain a polyadenylated tail at the 3′ end. LncRNAs have been confirmed to impact cancer initi- * Correspondence: [email protected] ation, development and progression and utilize a multi- 1 NHC Key Laboratory of Carcinogenesis, Department of Pathology, Xiangya tude of mechanisms mediated by specific sequences or Hospital, Central South University, Changsha 410080, China 2The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese structural motifs that bind DNA, RNA, or proteins [4, Ministry of Education, Department of Hematology, Xiangya Hospital, Central 5]. According to their position relative to neighboring South University, Changsha 410080, China protein-coding genes, lncRNAs are classified as sense, Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Zhang et al. Virology Journal (2020) 17:51 Page 2 of 8 antisense, bidirectional, intronic, or intergenic. The human and a high recurrence rate [24–26]. Considering the genome encodes thousands of lncRNAs that were previ- current situation, it is important to characterize sensitive ously considered ‘dark matter’ or ‘junk’ in the genome. and specific biomarkers for the early diagnosis of high-risk However, recent studies have illuminated the roles of individuals as well as the evaluation of NPC therapeutic ef- lncRNAs, and they are now considered important physio- fects. EBV infection is closely associated with NPC and is logical regulators of cell homeostasis, growth, and differen- present in almost 100% of low or non-differentiated NPC tiation [4, 5]. Now lncRNAs have been shown to play an cases [1, 2]. EBV can establish latent infection in NPC that elegant role in regulating gene expression at various levels, leads to changes in both intracellular metabolism and mo- and thus in affecting aspects of cellular homeostasis includ- lecular expression [1, 2, 27]. Therefore, EBV-related patho- ing proliferation, survival, migration and genomic stability genesis, biomarkers and therapeutics for NPC are worth [5–7]. Collective evidence has also identified the important exploring. role of lncRNAs in regulating antiviral responses [8, 9]. Persistent latent EBV infection has been found among al- In structure, lncRNAs are similar to mRNAs. While, un- most all NPC patients, indicating its etiological role in the like mRNAs which are normally cytoplasmic, lncRNAs initiation and progression of NPC. It is necessary to iden- show various subcellular distributions that can be detected tify potential biomarkers for the early-stage diagnosis, pro- in the nucleus, cytoplasm, or both. Moreover, lncRNAs gression and prognosis of NPC. According to a previous are usually tissue specific and less conserved than mRNAs study by Xiao-xiao Li et al., the application of next- [6, 10]. Some lncRNAs interact with the target genes and generation sequencing technology to 7 NPC tissue samples regulating their expression, thus mediating cell signaling and 7 normal nasopharyngeal tissue samples revealed that pathways [5, 6, 11]. Current researches indicate that 2192 lncRNAs were abnormally expressed in NPC and that lncRNAs are dysregulated in the infection of viruses. 62 lncRNAs trans-regulated genes were involved in EBV Howerver, the studies of lncRNAs in this field are still in infection [13]. In particular, several lncRNAs were down- infancy with regard to their functions. Some lncRNAs can regulated, including lncRNA-NR2F2 antisense RNA1 serve as scaffolds to regulate the transport or posttransla- (NR2F21), lncRNA-family with sequence similarity 95 tional modification of proteins, as well as play an import- member C (FAM95C), and long intergenic nonprotein ant regulatory role during viral infection such as triggering coding RNA 1106 (LINC01106), and some were upregu- the antiviral reaction [8, 12]. lated, including lncRNA-CH507-513H4.6, lncRNA-TH This review highlights lncRNAs associated with EBV AP9 antisense RNA 1 (THAP9-AS1), lncRNACH507-513 infection including EBV-related host lncRNAs and EBV- H4.3 and lncRNA-RP4-794H19.1 [13]. Sixty two genes po- encoded lncRNAs, focusing especially on their expres- tentially trans-regulated by the lncRNAs such as CD44 sion patterns and functions. (Hyaluronan/CD44 signaling plays an important role in head and neck squamous cell carcinoma progression) and Main text interleukin 1 receptor associated kinase 1 (IRAK1) are in- EBV-regulated host lncRNAs volved in the EBV infection pathway [13]. However, only a In recent years, lncRNAs have been shown to functionally few known lncRNAs have been functionally annotated. exert both positive and negative effects on innate immunity Therefore, lncRNA-related pathogenesis, biomarkers and and antiviral regulators. Some host lncRNAs show differen- therapeutics for NPC caused by EBV are worth further tial expression during EBV infection (Table 1), indicating exploring. their importance in the host response to EBV infection. Moreover, LINC00312, also known as NPC associated The aberrantly expressed host lncRNAs, designated as gene 7 (NAG7), is one of the earliest studied lncRNAs and EBV-regulated lncRNAs, can be regulated by or interacted acts as a tumor suppressor gene in NPC [28]. LINC00312 with EBV-encoded proteins and microRNAs [22]. expression was significantly different between NPC epi- thelium and various noncancerous nasopharyngeal epithe- EBV-regulated host lncRNAs may play roles in epithelial lia. LINC00312 can restrict the proliferation of NPC cells carcinomas and prevent the progression from G1 to S phase in the cell EBV infection contributes to a variety of human tumors, cycle, thus aggravating cell apoptosis. The expression of including epithelial