Long Non-coding RNAs in Gammaherpesvirus Infections: Their Roles in Tumorigenic Mechanisms

Abstract

Long non-coding RNAs (lncRNAs) regulate gene expression at the epigenetic, transcriptional, or posttranscriptional level by interacting with protein, DNA, and RNA. Emerging evidence suggests that various lncRNAs are abnormally expressed and play indispensable roles in virus-triggered cancers. Besides, a growing number of studies have shown that virus-encoded lncRNAs participate in tumorigenesis. However, the functions of most lncRNAs in tumors caused by oncogenic viruses and their underlying mechanisms remain largely unknown. In this review, we summarize current findings regarding lncRNAs involved in cancers caused by Epstein–Barr virus (EBV) and Kaposi’s sarcoma herpesvirus (KSHV). Additionally, we discuss the contribution of lncRNAs to tumor occurrence, development, invasion, and metastasis; the roles of lncRNAs in key signaling pathways and their potential as biomarkers and therapeutic targets for tumor diagnostics and treatment.

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…BART lncRNAs are involved in the epigenetic regulation of host gene expression and were demonstrated to inhibit expression of interferon beta 1 ( IFNB1 ) and CXCL8 genes. BHLF1 lncRNAs promote EBV replication but may also contribute to viral latency [ 312 , 313 , 314 ].…”

“…Comparison of EBV-positive tumors with control cells identified several cellular lncRNAs that were differentially expressed. Some of these cellular lncRNAs, such as H19, HOTAIR, and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1, aka nuclear-enriched abundant transcript 2; NEAT2) interfere with processes such as apoptosis, migration and invasion, proliferation, and DNA repair [ 45 , 313 , 314 , 315 ]. In conclusion, both EBV lncRNAs and EBV-induced cellular lncRNAs play indispensable roles in EBV-provoked malignancies.…”

“…Moreover, PAN lncRNA could interact with H3K27-specific demethylases UTX and JMJD3, and with the PRC2 components EZH2 and SUZ12. Hence, PAN lncRNA affects chromatin modification, resulting in altered host gene expression and seems to be required for efficient nuclear export of mRNA [ 45 , 128 , 314 , 316 ]. This viral-encoded lncRNA may play an essential role in KSHV-induced cancers.…”

“…Several cellular lncRNAs, including H19, growth arrest specific 5 (GAS5), deleted in lymphocytic leukemia 2 (DLEU2) and MALAT1 are abnormally expressed in KSHV-infected cells and aberrant expression of these lncRNAs has been associated with oncogenic processes such as proliferation, migration, invasion, cell survival and angiogenesis [ 314 ]. KSHV can also provoke changes in DNA methylation and histone modifications through induction of cellular lncRNA as shown by Yang and coworkers.…”

Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis

“…It is known that ncRNAs, in particular viral miRNAs and circRNAs, play a fundamental role in switching from lytic to latent phases, virus persistence and cell survival. Furthermore, viral circRNAs are expressed in infected cells but can be secreted into peripheral blood or transferred by extracellular vesicles to other cells to favor the spread of infection, with the advantage of being less recognizable by the host's immune system [35]. In spite of the multitude of ncRNAs encoded by viruses, only a small fraction have been functionally and structurally characterized.…”