Herpes virus microRNA expression and significance in serous ovarian cancer.

Deep Pandya,Giovanni Scambia,Candice Dowell-Martino,Marisa Mariani,Mirko Andreoli,Shiquan He,Paul Fiedler,Cristiano Ferlini,Steven Sieber,Mark Mchugh,Pierre Busson

doi:10.1371/journal.pone.0114750

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.

Highlights

Serous ovarian cancer (SEOC) is the most lethal gynecologic malignancy
The viral miRNA levels averaged significantly lower (TPM 11.8), as compared with a TPM mean of 45.6 in the SEOC (Fig. 1). These findings demonstrate that the expression of viral miRNAs is higher in SEOC than in noncancerous tissues
We demonstrate that the expression of total viral miRNAs is higher in SEOC as compared with normal tissues

Summary

Introduction

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. 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 vexing for ovarian cancer wherein extreme clonal heterogeneity is the norm and for which no driving mutations have been identified [2]

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Results

Conclusion