Identification of Circular RNAs as a Novel Biomarker for Ovarian Endometriosis

Abstract

Background:Endometriosis is a challenging disease with symptoms such as dysmenorrhea and infertility. However, its etiology is still vague and there is still no effective markers or treatment. This study aimed to profile the circular RNAs (circRNAs) expressed in eutopic endometrium from patients with ovarian endometriosis and explore potential clues to the pathogenesis of endometriosis, providing an evidence for clinical diagnosis and treatment.Methods:A total of 63 clinical samples, including control endometrium (n = 22) and eutopic endometrium (n = 41), were collected from Peking Union Medical College Hospital between May 1, 2016, and December 31, 2016. Of them, four samples in each group were used for circRNA microarray. Then, four upregulated circRNAs were screened out for quantitative real-time polymerase chain reaction (qRT-PCR) validation. After that, bioinformatics analysis was performed to predict miRNAs targeted by validated circRNAs and investigate the circRNA-miRNA-mRNA interactions.Results:Among 88 differentially expressed circRNAs, 11 were upregulated and 77 were downregulated in eutopic endometrium of patients with endometriosis. qRT-PCR validation results for two upregulated circRNAs (circ_0004712 and circ_0002198) matched the microarray results. The area under the receiver operating characteristic curve of circ_0002198 for distinguishing ovarian endometriosis was 0.846 (95% confidence interval [CI]: 0.752–0.939; P < 0.001) while that of circ_0004712 was 0.704 (95% CI: 0.571–0.837; P = 0.008). On the basis of target prediction, we depicted the molecular interactions between the identified circRNAs and their dominant target miRNAs, as well as constructed a circRNA-miRNA-mRNA network.Conclusions:This study provides evidence that circRNAs are differentially expressed between eutopic and normal endometrium, which suggests that circRNAs are candidate factors in the activation of endometriosis. circ_0002198 and circ_0004712 may be potential novel biomarkers for the diagnosis of ovarian endometriosis.

Circular RNA expression profiles and bioinformatics analysis in ovarian endometriosis

“…In this study, we investigated circRNA expression profiles in ecEM compared with euEM of endometriosis patients and identified 294 differentially expressed circRNAs, 146 upregulated and 148 downregulated. Most of those dysregulated circRNAs originate from exons or introns which are in accordance with previous researches (Shen et al, ; Xu et al, , ; Zhang, Ren, Xiao, Xia, & Fang, ). It has been reported that both exonic and intronic circRNAs may exert potential functions in gene regulation (Greene et al, ).…”

“…It has been reported that both exonic and intronic circRNAs may exert potential functions in gene regulation (Greene et al, ). Xu et al () revealed for the first time the circRNA expression patterns between women with and without endometriosis and found that the increased level of circ_0004712 and circ_0002198 could help identify the patients with endometriosis. Zhang, Ren, et al () assessed the expression profiles of circRNAs in endometriosis by microarray analysis and detected 2,237 circRNAs differentially expressed among ectopic endometrium (EC) (endometriotic lesions), paired eutopic endometrium (EU), and normal endometrium from women free of endometriosis, and qRT‐PCR validation suggested that downregulated circ_103470 and circ_101102 matched the microarray results.…”

Current biomarkers for the detection of endometriosis

“…[ 62 ] Another technique worth mentioning is miRNAs, which means small non-coding RNAs that repress translation thereby regulating the degree of gene expression. [ 44 ] Panir et al 's study [ 43 ] suggested that miRNA dysregulation may be involved in the pathophysiology of endometriosis and Xu et al [ 63 ] founded that circular RNAs are differentially expressed between eutopic and normal endometrium, but nowadays there is no non-coding RNA that can be used as reliable biomarkers for endometriosis no matter single or in panel. [ 44 ] However, with the continuous progress of experimental technologies, there will be more promising emerging technologies for us to try and explore in the future.…”

Diagnostic value of circular RNAs in female reproductive system diseases: A PRISMA‑compliant meta‑analysis

“…Unlike linear RNAs, circRNAs are protected against the effects of RNA enzymes due to their lack of free ends; these molecules are thus more stable compared with linear RNAs (5). With the development of RNA-seq analysis and bioinformatics technologies, recent studies have reported the use of circRNAs in the early detection and prognosis of certain types of cancer, such as gastric cancer (6), hepatocellular carcinoma (7), lung cancer (8), cervical squamous cell carcinoma (CSCC) and breast cancer (BRCA) (9), as well as a number of female reproductive system diseases including repeated implantation failure (10), preeclampsia (11) and ovarian endometriosis (12). Considering the association between hormone-responsive BRCA and the female reproductive system (13), this condition was included as a female reproductive system disease in the present meta-analysis.…”