Latent Epstein-Barr virus (EBV) infection is an etiological factor in the progression of several human epithelial malignancies such as nasopharyngeal carcinoma (NPC) and a subset of gastric carcinoma. Reports have shown that EBV produces several viral oncoproteins, yet their pathological roles in carcinogenesis are not fully elucidated. Studies on the recently discovered of EBV-encoded microRNAs (ebv-miRNAs) showed that these small molecules function as post-transcriptional gene regulators and may play a role in the carcinogenesis process. In NPC and EBV positive gastric carcinoma (EBVaGC), 22 viral miRNAs which are located in the long alternative splicing EBV transcripts, named BamH1 A rightward transcripts (BARTs), are abundantly expressed. The importance of several miR-BARTs in carcinogenesis has recently been demonstrated. These novel findings enhance our understanding of the oncogenic properties of EBV and may lead to a more effective design of therapeutic regimens to combat EBV-associated malignancies. This article will review the pathological roles of miR-BARTs in modulating the expression of cancer-related genes in both host and viral genomes. The expression of other small non-coding RNAs in NPC and the expression pattern of miR-BARTs in rare EBV-associated epithelial cancers will also be discussed.
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is overexpressed by pancreatic ductal adenocarcinoma (PDAC) cells and increases their aggressiveness. We identified microRNAs (miRs) that are regulated by EZH2 and studied their functions in PDAC cells.
Infection with the Epstein-Barr virus (EBV) is a strong predisposing factor in the development of nasopharyngeal carcinoma (NPC). Many viral gene products including EBNA1, LMP1, and LMP2 have been implicated in NPC tumorigenesis, although the de novo control of these viral oncoproteins remains largely unclear. The recent discovery of EBV-encoded viral microRNA (miRNA) in lymphoid malignancies has prompted us to examine the NPC-associated EBV miRNA. Using large-scale cloning analysis on EBV-positive NPC cells, two novel EBV miRNA, now named miR-BART21 and miR-BART22, were identified. These two EBV-encoded miRNA are abundantly expressed in most NPC samples. We found two nucleotide variations in the primary transcript of miR-BART22, which we experimentally confirmed to augment its biogenesis in vitro and thus may underline the high and consistent expression of miR-BART22 in NPC tumors. More importantly, we determined that the EBV latent membrane protein 2A (LMP2A) is the putative target of miR-BART22. LMP2A is a potent immunogenic viral antigen that is recognized by the cytotoxic T cells; down-modulation of LMP2A expression by miR-BART22 may permit escape of EBV-infected cells from host immune surveillance. Taken together, we demonstrated that two newly identified EBV-encoded miRNA are highly expressed in NPC. Specific sequence variations on the prevalent EBV strain in our locality might contribute to the higher miR-BART22 expression level in our NPC samples. Our findings emphasize the role of miR-BART22 in modulating LMP2A expression, which may facilitate NPC carcinogenesis by evading the host immune response.
A common GC polymorphism within miRNA-146a precursor region (rs2910164) has been associated with the risk of various cancers despite the underlying mechanism is unclear. In the current study, we aimed to examine the role of rs2910164 in the pathogenesis and predisposition to nasopharyngeal carcinoma (NPC). The GC polymorphism in 233 NPC patients, 173 matched controls and 3613 healthy elderly subjects in our locality were first determined using melting temperature (T(m))-shift allele-specific genotyping method. Results in our case-control study indicated that CC genotype was associated with the risk effect of NPC (adjusted odds ratio of GC + GG vs. CC, 0.49; 95% confidence interval, 0.35-0.69; P < 0.0001). Using real-time polymerase chain reaction (PCR) assay, we subsequently revealed that expressions of both miR-146a and its passenger strand (miR-146a*C or miR-146a*G) were increased in NPC samples (P < 0.001), albeit expression of miR-146a was not linked to the genotype. Furthermore, miR-146a*C in NPC was significantly increased in CC genotype (CC vs. GC, P = 0.038). Finally, we demonstrated by co-immunoprecipitation and luciferase reporter assays that all three miR-146a precursor-derived mature miRNAs interacted with Argonaute2 (Ago2) protein complex and could function as gene silencers. Taken together, our results showed that the variant C in rs2910164 was associated with the predisposition of NPC in Chinese population. This polymorphism may influence the risk of NPC by producing active mature miR-146a*C that regulate distinct set of target genes. These findings may enrich our understanding of how miRNA single nucleotide polymorphism affect NPC pathogenesis, and may have potential implications to improve NPC treatment in the future.
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