Herpes Virus MicroRNA Expression and Significance in Serous Ovarian Cancer

PLOS ONE, Dec 2019

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.

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Herpes Virus MicroRNA Expression and Significance in Serous Ovarian Cancer

December Herpes Virus MicroRNA Expression and Significance in Serous Ovarian Cancer Deep Pandya 0 1 Marisa Mariani 0 1 Mark McHugh 0 1 Mirko Andreoli 0 1 Steven Sieber 0 1 Shiquan He 0 1 Candice Dowell-Martino 0 1 Paul Fiedler 0 1 Giovanni Scambia 0 2 Cristiano Ferlini * 0 1 0 Editor: Pierre Busson , Gustave Roussy , France 1 Danbury Hospital Research Institute , Danbury, CT , United States of America, 2 Department of Gynecology, Catholic University of the Sacred Heart , Rome , Italy 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 miRData Availability: The authors confirm that all data underlying the findings are fully available without restriction. Analysis has been performed on the method. Viral miRNAs are more expressed in SEOC than in normal tissues. TCGA dataset which is freely accessible on the TCGA data portal (https://tcga-data.nci.nih.gov/ tcga/). Level 3 data are accessible without restrictions, while level 1 data and clinical information is accessible after an application is filed through the TCGA data portal. Policies for TCGA data access are explained at http:// Integrated analysis of gene and viral miRNAs expression suggests that miRcancergenome.nih.gov/abouttcga/policies/ policiesguidelines. - Funding: This work was partially supported by a grant from AIRC (Associazione Italiana Ricerca sul Cancro, IG11975), Associazione OPPO e le sue stanze ONLUS, by the Ruth C. Donovan Cancer Research Program and by a liberal donation from Mr. and Mrs. Ruggles. This work is dedicated to Monica DeFeo who lost her courageous battle against cancer at the young age of 53. Sponsors of the study did not have any role in the study conception and management. Competing Interests: The authors have declared that no competing interests exist. Serous ovarian cancer (SEOC) is the most lethal gynecologic malignancy. Due to its clinical indolence, the majority of patients are diagnosed late stage when surgery alone is insufficient to completely eradicate the tumor. As a consequence, chemotherapy is usually required to further control the disease. First-line chemotherapy for ovarian cancer typically includes a platinum agent (usually carboplatin) and a taxane (usually paclitaxel) [1]. Biomarkers which are prospectively predictive of sensitivity or resistance to chemotherapy are desperately needed to properly individualize therapeutic options and avoid toxic treatments for those patients who will be refractory to chemotherapy. The task of developing such biomarkers, problematic for all solid malignancies, is particularly vexing for ovarian cancer wherein extreme clonal heterogeneity is the norm and for which no driving mutations have been identified [2]. MicroRNAs (miRNAs) are a class of small, noncoding RNAs which regulate gene expression and protein translation and affect all aspects of cellular physiology. Accumulating evidence indicates that many miRNAs are aberrantly expressed in human cancers, and miRNA expression profiles have augmented prognostic information provided by traditional classification schemes related to stage and subtype [3, 4, 5]. Viruses also encode miRNAs and thereby affect functioning of infected cells. In mammals, viral infection is a potent trigger of the interferon response which inhibits viral replication and mitigates viral damage. Infection of mammalian cells by RNA viruses, except retroviruses, leads to the generation of long dsRNAs during the virus life cycle. DNA viruses produce dsRNAs by convergent transcription of their compact viral genomes. Viral dsRNA is a potent trigger of the interferon response which phosphorylates the translation factor eIF2a and leads to global translational arrest and apoptosis [6, 7, 8]. As an adaptive strategy, viruses have evolved a diverse array of countermeasures to block interferon production, and some of these rely on viral miRNAs as effectors of cellular control. All herpes viruses currently known (human and non-human) encode multiple miRNAs [9]. As an example, the hCMV miR-UL112-1 inhibits not only viral IE1 appearance but also cellular MICB expression to promote viral latency and avoid eradication by natural killer cells [10]. Therefore, it appears that herpes viruses are capable of hijacking the intracellular control of gene/protein expressio (...truncated)


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Deep Pandya, Marisa Mariani, Mark McHugh, Mirko Andreoli, Steven Sieber, Shiquan He, Candice Dowell-Martino, Paul Fiedler, Giovanni Scambia, Cristiano Ferlini. Herpes Virus MicroRNA Expression and Significance in Serous Ovarian Cancer, PLOS ONE, 2014, Volume 9, Issue 12, DOI: 10.1371/journal.pone.0114750