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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.

SUBMITTER: Pandya D

PROVIDER: S-EPMC4259392 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Herpes virus microRNA expression and significance in serous ovarian cancer.

Pandya Deep D Mariani Marisa M McHugh Mark M Andreoli Mirko M Sieber Steven S He Shiquan S Dowell-Martino Candice C Fiedler Paul P Scambia Giovanni G Ferlini Cristiano C

PloS one 20141208 12

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-valid ...[more]

PMID: 25485872

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Project description:High-grade serous ovarian cancer (HGSOC) is considered the most deadly and frequently occurring type of ovarian cancer and is associated with various molecular compositions and growth patterns. Evaluating the mRNA expression pattern of the organic anion transporters (OATPs) encoded by SLCO genes may allow for improved stratification of HGSOC patients for targeted invention. The expression of SLCO mRNA and genes coding for putative functionally related ABC-efflux pumps, enzymes, pregnane-X-receptor, ESR1 and ESR2 (coding for estrogen receptors ERα and ERß) and HER-2 were assessed using RT-qPCR. The expression levels were assessed in a cohort of 135 HGSOC patients to elucidate the independent impact of the expression pattern on the overall survival (OS). For identification of putative regulatory networks, Graphical Gaussian Models were constructed from the expression data with a tuning parameter K varying between meaningful borders (Pils et al., 2012; Auer et al., 2015, 2017; Kurman and Shih Ie, 2016; Karam et al., 2017; Labidi-Galy et al., 2017; Salomon-Perzynski et al., 2017; Sukhbaatar et al., 2017). The final value used (K = 4) was determined by maximizing the proportion of explained variation of the corresponding LASSO Cox regression model for OS. The following two networks of directly correlated genes were identified: (i) SLCO2B1 with ABCC3 implicated in estrogen homeostasis; and (ii) two ABC-efflux pumps in the immune regulation (ABCB2/ABCB3) with ABCC3 and HER-2. Combining LASSO Cox regression and univariate Cox regression analyses, SLCO5A1 coding for OATP5A1, an estrogen metabolite transporter located in the cytoplasm and plasma membranes of ovarian cancer cells, was identified as significant and independent prognostic factor for OS (HR = 0.68, CI 0.49-0.93; p = 0.031). Furthermore, results indicated the benefits of patients with high expression by adding 5.1% to the 12.8% of the proportion of explained variation (PEV) for clinicopathological parameters known for prognostic significance (FIGO stage, age and residual tumor after debulking). Additionally, overlap with previously described signatures that indicated a more favorable prognosis for ovarian cancer patients was shown for SLCO5A1, the network ABCB2/ABCB3/ABCC4/HER2 as well as ESR1. Furthermore, expression of SLCO2A1 and PGDH, which are important for PGE2 degradation, was associated with the non-miliary peritoneal tumor spreading. In conclusion, the present findings suggested that SLCOs and the related molecules identified as potential biomarkers in HGSOC may be useful for the development of novel therapeutic strategies.

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Herpes virus microRNA expression and significance in serous ovarian cancer.

Publications

Herpes virus microRNA expression and significance in serous ovarian cancer.

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