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Herpes virus microRNA expression and significance in serous ovarian cancer
Deep Pandya1, Marisa Mariani1, Mark McHugh1
1Danbury Hospital Research Institute, Danbury, CT, United States of America.
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.
Insights
Viral microRNAs (miRNAs) are elevated in serous ovarian cancer (SEOC). Specific viral miRNAs, miR-BART7 and miR-H25, serve as predictive biomarkers for SEOC patient outcomes and chemotherapy response.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- Serous ovarian cancer (SEOC) is a highly lethal gynecologic malignancy.
- MicroRNAs (miRNAs) are key regulators of gene expression, and viral miRNAs can influence host cell functions.
- The role of viral miRNAs in SEOC pathogenesis and prognosis is largely unexplored.
Purpose of the Study:
- To investigate the expression and clinical significance of viral miRNAs in SEOC.
- To determine the prognostic value of specific viral miRNAs (miR-BART7 and miR-H25) in SEOC.
- To explore the functional impact of viral miRNAs on chemotherapy resistance and patient survival.
Main Methods:
- Analysis of miRNA sequencing data from 487 SEOC patients (TCGA).
- Quantitative immunofluorescence validation of miR-H25 in 161 SEOC patients.
- In vitro studies using ovarian cancer cell lines with miR-H25 and miR-BART7 transfection.
- Gene expression analysis, cytotoxicity assays, and survival analysis (Cox, Kaplan-Meier).
Main Results:
- Viral miRNAs are significantly more expressed in SEOC tissues compared to normal tissues.
- Herpetic viral miRNAs, miR-BART7 (EBV) and miR-H25 (HSV-2), are significant predictors of SEOC outcome.
- miR-BART7 correlates with chemotherapy resistance and poorer survival, while miR-H25 is associated with improved long-term survival.
- miR-BART7 promotes cisplatin resistance; miR-H25 affects RNA processing and human miRNA expression.
Conclusions:
- This study is the first to link viral miRNA expression to ovarian cancer prognosis.
- Viral miRNAs, specifically miR-BART7 and miR-H25, are promising biomarkers for SEOC diagnosis and outcome prediction.
- Targeting viral miRNAs may offer novel therapeutic strategies to improve SEOC treatment outcomes.
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