Herpes Virus MicroRNA Expression and Significance in Serous Ovarian Cancer

Abstract

Serous ovarian cancer (SEOC) is the deadliest gynecologic malignancy. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate gene expression and protein translation. MiRNAs are also encoded by viruses with the intent of regulating their own genes and those of the infected cells. This is the first study assessing viral miRNAs in SEOC. MiRNAs sequencing data from 487 SEOC patients were downloaded from the TCGA website and analyzed through in-house sequencing pipeline. To cross-validate TCGA analysis, we measured the expression of miR-H25 by quantitative immunofluorescence in an additional cohort of 161 SEOC patients. Gene, miRNA expression, and cytotoxicity assay were performed on multiple ovarian cancer cell lines transfected with miR-H25 and miR-BART7. Outcome analysis was performed using multivariate Cox and Kaplan-Meier method. Viral miRNAs are more expressed in SEOC than in normal tissues. Moreover, Herpetic viral miRNAs (miR-BART7 from EBV and miR-H25 from HSV-2) are significant and predictive biomarkers of outcome in multivariate Cox analysis. MiR-BART7 correlates with resistance to first line chemotherapy and early death, whereas miR-H25 appears to impart a protective effect and long term survival. Integrated analysis of gene and viral miRNAs expression suggests that miR-BART7 induces directly cisplatin-resistance, while miR-H25 alters RNA processing and affects the expression of noxious human miRNAs such as miR-143. This is the first investigation linking viral miRNA expression to ovarian cancer outcome. Viral miRNAs can be useful to develop biomarkers for early diagnosis and as a potential therapeutic tool to reduce SEOC lethality.

Epstein-Barr Virus MicroRNA Expression Increases Aggressiveness of Solid Malignancies

“…We postulated that multiple parallel sequencing, employed to investigate the expression of miRNAs in TCGA datasets [ 11 ], had overlooked herpetic viral miRNAs in human specimens due to the fact that only human (and not viral) miRNAs were included in the reference miRNA database. In a recently published study conducted on a large cohort of serous epithelial ovarian cancer patients, we demonstrated that this is indeed the case [ 12 ]. Herpetic miRNAs are not only relatively abundant in ovarian cancer tissues, they also drive clinical outcome.…”

Factors in Oncogenesis: Viral Infections in Ovarian Cancer

“…EBV appears to play a direct oncogenic role through genome-wide alteration of promoter methylation and expression of miRNA and genes involved in cell motility and transformation pathways [165,166]. EBV DNA has been detected in approximately 5%-7% of EOC tissue samples [74,76], while no DNA virus transcripts were detected in ovarian serous cystadenocarcinoma [75]. Moreover, no association between EOC and EBV antibody levels has been found [167].…”

“…It has been suggested that primary EBV infection at a later age may play a role in the etiology of ovarian cancer. An EBV viral miRNA, miR-BART7, induces cisplatin resistance and develops resistance to first-line chemotherapy and early death in patients with serous OC [76]. EBV nuclear antigens (EBNAs) and membrane proteins (LMP1, LMP2A, and LMP2B) are known target the p53 family in lymphomas and nasopharyngeal and gastric cancer [168].…”

High expression of JC polyomavirus-encoded microRNAs in progressive multifocal leukoencephalopathy tissues and its repressive role in virus replication

“…To our knowledge, this is the first report showing high expression and clear localization of virus-encoded miRNA in virus-associated disease tissues by in situ hybridization. Although several previous reports have described the in situ detection of viral miRNAs such as HSV2 [37], EBV [38,39], and HPV [40], no clear evidence of miRNA localization in tissue samples has been demonstrated.…”