Long non-coding RNAs in Epstein-Barr virus-related cancer

Abstract

Epstein Barr-virus (EBV) is related to several cancers. Long non-coding RNAs (lncRNAs) act by regulating target genes and are involved in tumourigenesis. However, the role of lncRNAs in EBV-associated cancers is rarely reported. Understanding the role and mechanism of lncRNAs in EBV-associated cancers may contribute to diagnosis, prognosis and clinical therapy in the future. EBV encodes not only miRNAs, but also BART lncRNAs during latency and the BHLF1 lncRNA during both the latent and lytic phases. These lncRNAs can be targeted regulate inflammation, invasion, and migration and thus tumourigenesis. The products of EBV also directly and indirectly regulate host lncRNAs, including LINC00312, NORAD CYTOR, SHNG8, SHNG5, MINCR, lncRNA-BC200, LINC00672, MALATI1, LINC00982, LINC02067, IGFBP7-AS1, LOC100505716, LOC100128494, NAG7 and RP4-794H19.1, to facilitate tumourigenesis using different mechanisms. Additionally, lncRNAs have been previously validated to interact with microRNAs (miRNAs), and lncRNAs and miRNAs mutually suppress each other. The EBV-miR-BART6-3p/LOC553103/STMN1 axis inhibits EBV-associated tumour cell proliferation. Additionally, H. pylori-EBV co-infection promotes inflammatory lesions and results in EMT. HPV-EBV co-infection inhibits the transition from latency to lytic replication. KSHV-EBV co-infection aggravates tumourigenesis in huNSG mice. COVID-19-EBV co-infection may activate the immune system to destroy a tumour, although this situation is rare and the mechanism requires further confirmation. Hopefully, this information will shed some light on tumour therapy strategies tumourigenesis. Additionally, this strategy benefits for infected patients by preventing latency to lytic replication. Understanding the role and expression of lnRNAs in these two phases of EBV is critical to control the transition from latency to the lytic replication phase. This review presents differential expressed lncRNAs in EBV-associated cancers and provides resources to aid in developing superior strategies for clinical therapy.

Keywords: EBV latent infection; EBV lytic infection; Epstein–Barr virus; Long non-coding RNAs (lncRNAs); Tumourigenesis.

Fig. 1

Simplified summary of EBV-encoded genes during latent and lytic phases. Latent infection genes are encoded in the latent phase, such as LMP, EBNA, EBER, and BART. Immediate-early genes, including BZLF1 and BRLF1, encode proteins that promote the transition to EBV lytic infection. Early genes are associated with virus replication and include BALF2, BALF5, BORF2, BGLF5, NARF1, BSMLF1, BXLF1, BHRF1, and BCFR1. Late genes, including BLLF1, BALF4, BXLF2, and BCRF1, mainly encode virus structural proteins. Immediate-early genes, early genes, and late genes are expressed during the lytic phase

Fig. 2

Role of BART lncRNAs encoded by EBV. BART lncRNAs inhibit the host immune response by blocking Pol II, and the genes involved in the immune response cannot be transcribed. BART lncRNAs inhibit MAVS to contribute to chromatin remodelling. BART lncRNAs promote the activation of IKZF3 to regulate the cellular redox state and apoptosis. BART lncRNAs induce hypermethylation via Septin. The feedback loop among BARTs, NF-κB, and LMP1 facilitates the persistence of latency

Fig. 3

Host lncRNAs involved in EBV-associated cancer. The lncRNAs MINCR, SNHG8, CYTOR, LOC554103, and RP4-793H19.1 are upregulated, and the lncRNAs LIN00312 (also known as NAG7 and ERR-10), NORAD, LINCOO982, LOC10028494, LOC100505716, IGFBP7-AS1, and LINCO2067 are downregulated in EBV-associated cancer. Both upregulated and downregulated lncRNAs are involved in tumourigenesis

Fig. 4

Flowchart of the research methodology for each study. The differential expression of most lncRNAs was identified by NGS. LOC553103 was identified by microarray. LINC003112 was identified by positional candidate cloning. BART lncRNA was knocked down using the Gapmers technique for further study. BHLF1 lncRNA was identified by FISH. CYTOR was knocked down by CRISPRi, and NORAD was overexpressed by CRISPRa. MINCR was further evaluated using RNAi. Sixty-two lncRNAs and RP4-794H19.1 were predicted to be involved in their target pathways by KEGG and GO analyses. SNHG8, IGFB7-AS1, MIR143HG, H19, and RNU12 were predicted to be target genes using starBase v2.0, lncRNA and Disease Database and DIANA LncBASE software. LOC553103 was further assessed using siRNA and RIP. LINC003112 was further studied using an overexpression plasmid and was identified in tissue samples for analysis relevant to ISH. NGS next-generation sequencing, FISH fluorescence in situ hybridization, RNAi RNA interference, CRISPRi CRISPR interference, CRISPRa CRISPR activation, RIP RNA-binding protein immunoprecipitation, ISH in situ hybridization

Fig. 5

EBV co-infectious agents. H. pylori-EBV co-infection not only enhances the inflammatory process but also promotes immune evasion, EMT and bacterial growth and inhibits apoptosis. HPV–EBV co-infection inhibits EBV lytic replication and shifts EBV towards the latent phase. KSHV–EBV co-infection aggravates tumourigenesis by mutually reinforcing the persistence of each latent genome and altering cell proliferation