Clinical relevance of circulating cell-free microRNAs in ovarian cancer

Abstract

Ovarian cancer is the leading cause of death among gynecologic malignancies. Since ovarian cancer develops asymptomatically, it is often diagnosed at an advanced and incurable stage. Despite many years of research, there is still a lack of reliable diagnostic markers and methods for early detection and screening. Recently, it was discovered that cell-free microRNAs (miRNAs) circulate in the body fluids of healthy and diseased patients, suggesting that they may serve as a novel diagnostic marker. This review summarizes the current knowledge regarding the potential clinical relevance of circulating cell-free miRNA for ovarian cancer diagnosis, prognosis, and therapeutics. Despite the high levels of ribonucleases in many types of body fluids, most of the circulating miRNAs are packaged in microvesicles, exosomes, or apoptotic bodies, are binding to RNA-binding protein such as argonaute 2 or lipoprotein complexes, and are thus highly stable. Cell-free miRNA signatures are known to be parallel to those from the originating tumor cells, indicating that circulating miRNA profiles accurately reflect the tumor profiles. Since it is well established that the dysregulation of miRNAs is involved in the tumorigenesis of ovarian cancer, cell-free miRNAs circulating in body fluids such as serum, plasma, whole blood, and urine may reflect not only the existence of ovarian cancer but also tumor histology, stage, and prognoses of the patients. Several groups have successfully demonstrated that serum or plasma miRNAs are able to discriminate patients with ovarian cancer patients from healthy controls, suggesting that the addition of these miRNAs to current testing regimens may improve diagnosis accuracies for ovarian cancer. Furthermore, recent studies have revealed that changes in levels of cell-free circulating miRNAs are associated with the condition of cancer patients. Discrepancies between the results across studies due to the lack of an established endogenous miRNA control to normalize for circulating miRNA levels, as well as differing extraction and quantification methods, are the pitfalls to be resolved before clinical application. There is still a long way, however, before this can be achieved, and further evidence would make it possible to apply circulating cell-free miRNAs not only as biomarkers but also as potential therapeutic targets for ovarian cancer in the future.

A method for extracting and characterizing RNA from urine: For downstream PCR and RNAseq analysis

“…Based on a literature review we expected to find miR-146a and miR-29a in urine due to their previous association with ovarian cancer and previous findings of their presence in exRNA samples (23,24,37,38). Neither of these microRNAs were highly expressed in any of the eight samples as detected by NGS.…”

“…High throughput sequencing studies have fueled the search for novel ncRNA biomarkers from accessible samples including serum, plasma and urine (3,24). The unexpected stability of exRNA and new technologies to deep sequence RNA have led to an explosion of new biomarker studies focusing on ncRNAs in accessible samples (1–4).…”

“…Studies of microRNAs in ovarian cancer have delineated a set of differentially expressed microRNAs that are expected to regulate key tumor suppressors such as BRCA1 (19). Such oncomirs would be expected to be over expressed in biological fluids from cancer patients and have been studied in tissue, serum, ascites fluid and urine from ovarian cancer patients (20–24). microRNAs associated with extracellular vesicles (EVs) are also found in urine from healthy volunteers (25,26).…”

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment

“…Specific miRNA-based signatures or networks have been identified in epithelial ovarian cancers characterized by a poor prognosis, and have the potential to serve as prognostic markers in both early and advanced stages of the disease [130,131,132]. In addition, stable circulating cell-free miRNAs that closely mimic the miRNA profiles of tumor have been isolated from the serum and plasma of women with ovarian cancer [133]. Furthermore, distinctly different circulating miRNA signatures were observed in women with ovarian cancer compared with healthy controls, suggesting that circulating miRNAs may be useful as markers for early detection, as well as for disease prognosis [133,134].…”

Circulating biomarkers in epithelial ovarian cancer diagnosis: from present to future perspective

“…To explore in more depth the current knowledge of miRs as potential biomarkers for OC, we suggest to read three recent reviews on this topic (107)(108)(109).…”