Elevated levels of circulating microRNA-200 family members correlate with serous epithelial ovarian cancer

Abstract

BackgroundThere is a critical need for improved diagnostic markers for high grade serous epithelial ovarian cancer (SEOC). MicroRNAs are stable in the circulation and may have utility as biomarkers of malignancy. We investigated whether levels of serum microRNA could discriminate women with high-grade SEOC from age matched healthy volunteers.MethodsTo identify microRNA of interest, microRNA expression profiling was performed on 4 SEOC cell lines and normal human ovarian surface epithelial cells. Total RNA was extracted from 500 μL aliquots of serum collected from patients with SEOC (n = 28) and age-matched healthy donors (n = 28). Serum microRNA levels were assessed by quantitative RT-PCR following preamplification.ResultsmicroRNA (miR)-182, miR-200a, miR-200b and miR-200c were highly overexpressed in the SEOC cell lines relative to normal human ovarian surface epithelial cells and were assessed in RNA extracted from serum as candidate biomarkers. miR-103, miR-92a and miR -638 had relatively invariant expression across all ovarian cell lines, and with small-nucleolar C/D box 48 (RNU48) were assessed in RNA extracted from serum as candidate endogenous normalizers. No correlation between serum levels and age were observed (age range 30-79 years) for any of these microRNA or RNU48. Individually, miR-200a, miR-200b and miR-200c normalized to serum volume and miR-103 were significantly higher in serum of the SEOC cohort (P < 0.05; 0.05; 0.0005 respectively) and in combination, miR-200b + miR-200c normalized to serum volume and miR-103 was the best predictive classifier of SEOC (ROC-AUC = 0.784). This predictive model (miR-200b + miR-200c) was further confirmed by leave one out cross validation (AUC = 0.784).ConclusionsWe identified serum microRNAs able to discriminate patients with high grade SEOC from age-matched healthy controls. The addition of these microRNAs to current testing regimes may improve diagnosis for women with SEOC.

Expression analysis of differentially expressed miRNAs in male and female chicken embryos

“…Although some predicted targets of all these four miRNAs (listed in Table 2) were found to be involved in the developmental process of the animal gonad and maintenance of gonadal functions, they were not reported to have any function in animal gonadal development in previous studies except for miR-200b. In present study, we found that miR-200b was universally expressed in some tissues in E4.5 chicken embryo, which was similar to the results of other studies in zebrafish (Wienholds et al, 2005) and chicken (Darnell et al, 2006). Accordingly, miR-200b has been shown to have important functions in many organs, including the development of olfactory bulb and palate (Bak et al, 2008;Shin et al, 2012), renal tubule maturation (Patel et al, 2012), some cancer development (Kan et al, 2012;Kurashige et al, 2012;Dai et al, 2013), etc. Recently, miR200b and its two other family members were observed to be highly overexpressed in the SEOC miRNA expression analysis in chicken embryos (serous epithelial ovarian cancer) cell lines, and suggested to correlate with serous epithelial ovarian cancer (Kan et al, 2012).…”

“…Accordingly, miR-200b has been shown to have important functions in many organs, including the development of olfactory bulb and palate (Bak et al, 2008;Shin et al, 2012), renal tubule maturation (Patel et al, 2012), some cancer development (Kan et al, 2012;Kurashige et al, 2012;Dai et al, 2013), etc. Recently, miR200b and its two other family members were observed to be highly overexpressed in the SEOC miRNA expression analysis in chicken embryos (serous epithelial ovarian cancer) cell lines, and suggested to correlate with serous epithelial ovarian cancer (Kan et al, 2012). This conclusion indicated that the normal expression of miR-200b is important to ovary development.…”

Circulating U2 Small Nuclear RNA Fragments as a Novel Diagnostic Tool for Patients with Epithelial Ovarian Cancer

“…To date, miRNA-based biomarkers have been proposed for several different cancer types including lung cancer, breast cancer, and gastrointestinal malignancies (10,11 ). For ovarian cancer, only 3 pilot studies so far have investigated miRNA candidates that are differentially expressed in ovarian cancer tissue or ovarian cancer cell lines for their presence in the circulation (12)(13)(14). Another study compared the expression pattern of exosomal, serum-derived miRNAs with the miRNA pattern of the corresponding primary tumor (15 ).…”

Expression of miR-146a in patients with ovarian cancer and its clinical significance

“…Let-7f was identified as a predictive factor for ovarian cancer prognosis (20). A predictive model based on the serum expression levels of miR-200b/miR-200c was able to discriminate between normal controls and age-matched patients with high-grade serous ovarian cancer (21). A number of other miRs were studied, and the levels of these miRs were correlated with the hazard ratio for patient survival or tumor recurrence (22).…”