Expression and clinical value of circRNAs in serum extracellular vesicles for gastric cancer

Abstract

ObjectiveAt present, there are still no effective diagnosis methods for gastric cancer (GC). Increasing evidences indicate that Extracellular Vesicle circular RNAs (EV circRNAs) play a crucial role in several diseases. However, their correlations with GC are not clarified. This study aims to investigate the expression profile of serum EV circRNAs in GC and evaluate its potential clinical value.MethodsHigh-throughput RNA sequencing (RNA-seq) was used to assess circRNA expression profiles between 4 patients with GC and 4 healthy controls. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were employed to determine the biological functions of differentially expressed (DE) circRNAs. A circRNA-miRNA-mRNA network was constructed using bioinformatics tools. Reverse transcription-quantitative polymerase chain reaction (RT-q)PCR was used to validate the dysregulated circRNAs. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value of circRNAs for GC.ResultsA total of 4692 circRNAs were detected in the serum EVs of healthy controls and patients with GC, most of which were novel (98%) and intergenic (52%). 7 circRNAs were upregulated and 4 circRNAs were downregulated (|log2Fold Change| > 2, P < 0.05). GO and KEGG pathway enrichment analyses revealed that DE circRNAs were primarily involved in glutathione metabolism, protein folding, and drug metabolism-cytochrome P450. Of these, 3 circRNAs (Chr10q11, Chr1p11, and Chr7q11) were identified to be significantly overexpressed in patients with GC compared with healthy controls using RT-qPCR. The combination of 3 EV circRNAs and carcinoembryonic antigen (CEA) produced an area under the curve (AUC) of 0.866 (95%CI: 0.803-0.915) with a sensitivity and specificity of 80.4% and 81.8%, respectively. Additionally, the expression levels of 3 EV circRNAs were significantly correlated with tumor size, lymph node metastasis, and TNM stage. The circRNA-miRNA-mRNA network showed that the 3 identified circRNAs were predicted to interact with 13 miRNAs and 91 mRNAs.ConclusionOur results illustrate that the panel of EV circRNAs in serum are aberrantly expressed and may act as the suitable biomarkers for gastric cancer.

Extracellular vesicle biomarkers in circulation for the diagnosis of gastric cancer: A systematic review and meta‑analysis

“…This result suggested that miRNAs are more promising diagnostic biomarkers for GC, comparing to lncRNAs. A total of three studies reported five EV circRNAs that had a powerful diagnostic efficiency for GC (20,27,34). circRNAs are a class of RNA with a unique closed loop-structure structure without 5' and 3' ends, which increases RNase R resistance compared with other non-coding RNAs (ncRNAs) (54,55).…”

“…A total of 26 studies analyzed the diagnostic value of RNAs for GC: MiRNAs in 13 studies (22,24,25,(28)(29)(30)(31)(32)(33)37,40,42,44,45), four of which performed validation tests (25,29,31,44); lncRNAs in nine studies (19,20,23,26,35,38,39,41,45); circular RNAs (circRNAs) in three studies (21,27,34); P-element induced wimpy testis-interacting RNAs (piRNAs) in one study (42); mRNA in one study (43); and a single study reported the diagnostic value of protein (36). A total of nine studies set a diagnostic cut-off value, which was determined using the Youden Index (19,23,27,31,33,34,39,41,45). A total of five studies reported the diagnostic value of RNA panels (25,27,29,31,…”

“…A total of nine studies set a diagnostic cut-off value, which was determined using the Youden Index (19,23,27,31,33,34,39,41,45). A total of five studies reported the diagnostic value of RNA panels (25,27,29,31,40), two of which performed validation testing (25,29). A total of six studies reported the diagnostic performance of EV biomarkers for early stage GC (stage I/II) (31,33,34,36,38,41), of which one study performed validation testing (31).…”

Global progress and future prospects of early gastric cancer screening

“…The RNA Pol II transcript, lncRNA-GCI, has also demonstrated significant potential as an early detection biomarker for GC and holds promise as a disease progression biomarker 188 . Another study discovered that patients with gastric cancer exhibit significantly elevated levels of three serum EV-derived circRNAs (Chr10q11, Chr1p11, and Chr7q11) compared to those of healthy controls 189 . Furthermore, when used in conjunction with CEA, the combination resulted in an area under the curve (AUC) of 0.866 (95% CI: 0.803-0.915) with a corresponding sensitivity and a specificity of 80.4% and 81.8%, respectively 189 .…”

Nomograms incorporating hsa_circ_0029325 highly expressed in exosomes of hepatocellular carcinoma predict the postoperative outcomes

“…Our previous laboratory data initially explored the predictive value of circRNA in exosomes in HCC [ 16 ]. Recently, altered of extracellular vesicle circRNA expression profiles have demonstrated their predictive value in a variety of cancers, such as colorectal cancer [ 17 ], gastric cancer [ 18 ] and esophageal squamous cell cancer [ 19 ]. However, there is no relevant study on its predictive value in HCC.…”