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MiRNA-200a/c as potential biomarker in epithelial ovarian cancer (EOC): evidence based on miRNA meta-signature and clinical investigations.

ABSTRACT: Extensive effort has been put on miRNA expression signatures in epithelial ovarian cancer (EOC). Unfortunately, consistent conclusion rarely yielded from diverse studies, mainly due to the high inter-lab variability and small sample sizes. To overcome above limitations, an integrated analysis of miRNA expression signature was performed by employing Robust Rank Aggregation (RRA) method. Diagnostic analysis, Kaplan-Meier survival curves and pathway enrichment analysis were used to investigate the clinical values and biological functions of meta-signature miRNAs. A total of 519 EOC and 248 noncancerous samples were included. Seven mostly dysregulated miRNAs were identified by RRA method and two miRNAs (miR-200a-3p and miR-200c-3p) remained statistically significant after Bonferroni-correction. Diagnostic meta-analysis showed reliable diagnostic capacity of miR-200a-3p (with a pooled sensitivity of 0.84 and specificity of 0.83) and miR-200c-3p (with a pooled sensitivity of 0.75 and specificity of 0.66) for EOC. Pathway enrichment analysis and expression correlation analysis suggested miR-200a/c might contribute EOC progression by affecting cellular adhesion process. Kaplan-Meier survival analysis based on two independent cohorts revealed a strong association between miR-200a/c and overall survival in EOC patients. miR-200a/c was identified as the mostly dysregulated miRNAs in EOC and might be novel diagnostic and prognostic biomarkers for patients with EOC.

SUBMITTER: Teng Y

PROVIDER: S-EPMC5348417 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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miRNA-200a/c as potential biomarker in epithelial ovarian cancer (EOC): evidence based on miRNA meta-signature and clinical investigations.

Teng Yue Y Su Xuan X Zhang Xing X Zhang Yan Y Li Chen C Niu Wenquan W Liu Chang C Qu Kai K

Oncotarget 20161201 49

Extensive effort has been put on miRNA expression signatures in epithelial ovarian cancer (EOC). Unfortunately, consistent conclusion rarely yielded from diverse studies, mainly due to the high inter-lab variability and small sample sizes. To overcome above limitations, an integrated analysis of miRNA expression signature was performed by employing Robust Rank Aggregation (RRA) method. Diagnostic analysis, Kaplan-Meier survival curves and pathway enrichment analysis were used to investigate the ...[more]

PMID: 27835595

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Project description:Background Ovarian cancer is the most lethal tumor of the female reproductive system. Establishing a methodology to screen and diagnose ovarian cancer in the early stage is important. Exosomes have been shown to be loaded with tumor-associated molecules. In this study, we compared the proteins loaded in exosomes from the peripheral circulation of epithelial ovarian carcinoma (EOC) patients and controls. Methods Exosomes were purified via ultracentrifugation plus 0.22 µm filtration from the blood of EOC patients and patients with pelvic floor dysfunction (PFD). Tumor tissues and normal ovarian tissues were also obtained. Proteomic analyses of exosomes and tumor/normal ovarian tissues were performed with isobaric tags for relative and absolute quantitation (iTRAQ) and high-performance liquid chromatography/mass spectrometry (HPLC/MS) analyses. The LocDB (http://www.rostlab.org/services/locDB), PANTHER (http://www.pantherdb.org/) and Vesiclepedia databases were used for biological information analysis. Results We identified 408 differentially expressed proteins in exosomes from EOC patients and noncancer controls. Furthermore, we identified 954 differentially expressed proteins from ovarian cancer tissues and normal ovarian tissues. Thirty-five proteins exhibited upregulation in both cancer patient exosomes and cancer tissues. Among these 35 proteins, eight proteins (chloride intracellular channel protein 4, serine/threonine-protein kinase 1, aminoacyl tRNA synthetase complex-interacting multifunctional protein 1, sorting nexin-3, protein FAM49B, fermitin family homolog 3, tubulin beta-3 chain and lactotransferrin) were confirmed in both exosome databases and other studies. Conclusions We isolated exosomes from the peripheral blood of EOC patients and noncancer controls and identified 35 proteins that were upregulated in both EOC patient exosomes and ovarian cancer tissues. Comparisons with the exosome molecular databases and other studies identified eight proteins as potential tumor markers, which might offer new tools for the early diagnosis of ovarian cancer.

Project description:BackgroundDefective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.MethodsIn total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.ResultsThe most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).ConclusionThese results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

Dataset Information

MiRNA-200a/c as potential biomarker in epithelial ovarian cancer (EOC): evidence based on miRNA meta-signature and clinical investigations.

Publications

miRNA-200a/c as potential biomarker in epithelial ovarian cancer (EOC): evidence based on miRNA meta-signature and clinical investigations.

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