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.
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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)