A two-circular RNA signature as a noninvasive diagnostic biomarker for lung adenocarcinoma

Abstract

Background Recently, circular RNAs (circRNAs) have been reported to be microRNA sponges and play essential roles in cancer development. This study aimed to evaluate whether circulating circRNAs could be used as diagnostic biomarkers for lung adenocarcinoma (LUAD). Methods The Gene Expression Omnibus (GEO) dataset was used to investigate differentially expressed circRNAs (DEcircRNAs) in paired LUAD tissues and adjacent nontumor tissues. The expression levels of the host genes were analyzed in The Cancer Genome Atlas (TCGA)-LUAD dataset, and the prognostic value was assessed using the Kaplan–Meier plotter. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression of candidate circRNAs in the LUAD plasma and cells. The CCK8 assay was used to measure the function of circRNAs in cell proliferation. Competing endogenous RNA (ceRNA) network, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the possible mechanisms and functions of circRNAs in LUAD. Results Two upregulated and two downregulated circRNAs were identified as candidate circRNAs using bioinformatics analysis. qRT-PCR demonstrated that hsa_circ_0005962 was upregulated in LUAD plasma and cells, whereas hsa_circ_0086414 was downregulated. Receiver operating characteristic (ROC) curve analysis confirmed that a signature comprising the two circRNAs had good diagnostic potential, with an area under the ROC curve (AUC) of 0.81 ( P < 0.0001). In addition, we observed that overexpression of plasma hsa_circ_0086414 was related to EGFR mutations ( P = 0.001). Plasma hsa_circ_0005962 displayed significantly different expression before and after surgery in patients with LUAD ( P < 0.0001). In vitro experiments suggested that hsa_circ_0005962 promoted LUAD cell proliferation. For future studies, we predicted the circRNA-miRNA-mRNA network for hsa_circ_0005962. Bioinformatics analysis revealed that hsa_circ_0005962 might be involved in LUAD development. Conclusion A circRNA signature was identified as a potential noninvasive biomarker for LUAD diagnosis. Electronic supplementary material The online version of this article (10.1186/s12967-019-1800-z) contains supplementary material, which is available to authorized users.

Circular RNA SMARCA5 may serve as a tumor suppressor in non‐small cell lung cancer

“…Previous studies have demonstrated that circRNAs may be closely connected with the development cancers . Among them, circ‐SMARCA5, the circRNA derives from exons 15 and 16 of SMARCA5 gene, is found to be related to the disease progression in a few cancers .…”

“…Although these studies display downregulated expressions of circ‐SMARCA5 in some cancers, the involvement of circ‐SMARCA5 in lung cancer has not been clearly clarified, and only one study shows that circ‐SMARCA5 is downregulated in NSCLC tissues compared to the adjacent normal tissues, and it inhibits cell proliferation, migration as well as invasion in NSCLC cell lines . Some recent studies have implied that non‐coding RNAs, especially circRNAs, play crucial roles in pathology and progression of NSCLC . For example, long non‐coding RNA KDM5B anti‐sense RNA 1 enhances tumor progression in NSCLC; circular RNA F‐circSR derived from SLC34A2‐ROS1 fusion gene enhances cell migration in NSCLC; overexpression of circular RNA FARSA promotes NSCLC cell migration and invasion .…”

Circ_0005962 functions as an oncogene to aggravate non-small cell lung cancer progression via circ_0005962/miR-382-5p/PDK4 regulatory network

“…Despite the fact that the role of several circRNAs was partly characterized, there were still existing circRNAs lacking functional exploration. A previous study predicted differentially expressed circRNAs in lung adenocarcinoma using Gene Expression Omnibus (GEO) dataset and found that circ_0005962 was highly expressed in lung adenocarcinoma plasma and cells (Liu et al, 2019). In view of this finding, we speculated that dysregulation of circ_0005962 might be associated with the malignant progression of NSCLC.…”

“…CircRNA F-circEA-2a contributed to cell migration and invasion but had little role in cell proliferation (Tan et al, 2018). A former study obtained dozens of circRNAs through the CircBase database and CSCD database for comparison between lung adenocarcinoma tissues and paired non-tumor tissues (Liu et al, 2019), and circ_0005962, back-spliced from tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta (YWHAZ), was one of the significantly upregulated circRNAs and had valuable prognostic significance. However, the understanding of the specific roles of circ_0005962 in NSCLC remains lacking and requires further exploration.…”

<p>Biological Roles and Mechanisms of Circular RNA in Human Cancers</p>

“…30 Increasing evidence suggested that circRNA might participate in the cell proliferation, migration and invasion of lung cancer, and serve as an important diagnostic marker for the treatment of lung cancer. [31][32][33][34][35][36][37] For example, circNOL10 increased the expression of transcription factor sex comb on midleg-like 1 (SCML1) by inhibiting ubiquitination and regulating the humanin (HN) polypeptide family through affecting multiple signaling pathways. This ultimately inhibited proliferation and induced cell cycle arrest in lung cancer cells.…”