Identification of the circRNA-miRNA-mRNA regulatory network and its prognostic effect in colorectal cancer

Abstract

BACKGROUND The high morbidity and mortality of colorectal cancer (CRC) have posed great threats to human health. Circular RNA (CircRNA) and microRNA (miRNA), acting as competing endogenous RNAs (ceRNAs), have been found to play vital roles in carcinogenesis. However, the biological function of ceRNAs in CRC pathogenesis and prognosis remains largely unexplored. AIM To identify the CRC-specific circRNA-miRNA-mRNA regulatory network and uncover the subnetwork associated with its prognosis. METHODS CircRNAs, miRNAs and mRNAs differentially expressed (DE) in CRC tissues were selected by expression file analysis in the Gene Expression Omnibus (GEO) database, and the downstream target molecules of circRNAs and miRNAs were predicted. Then, the intersection of differentially expressed RNA molecules with the predicted targets was determined to obtain a ceRNA network. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted to elucidate the possible mechanism of pathogenesis. A survival analysis using the gene profiles and clinical information in The Cancer Genome Atlas (TCGA) database was performed to identify the mRNAs associated with the clinical outcome of CRC patients and construct a prognostic subnetwork. RESULTS We downloaded three datasets (GSE126095, GSE41655 and GSE41657) of large-scale CRC samples from the GEO database. There were 55 DEcircRNAs, 114 DEmiRNAs and 267 DEmRNAs in CRC tissues compared with normal tissues. After intersecting these molecules with predicted targets, 19 circRNAs, 13 miRNAs and 28 mRNAs were chosen to develop a circRNA-miRNA-mRNA network. GO and KEGG functional enrichment analyses indicated that the retinol metabolic process, leukocyte chemotaxis, extracellular matrix remodeling, endoplasmic reticulum stress, alcohol dehydrogenase activity, gastric acid secretion, nitrogen metabolism and NOD-like receptor signaling pathway might participate in the tumorigenesis of CRC. After verifying the identified mRNA effect in the TCGA database, we finally recognized 3 mRNAs ( CA2, ITLN1 and LRRC19 ) that were significantly associated with the overall survival of CRC patients and constructed a ceRNA subnetwork including 5 circRNAs (hsa_circ_0080210, hsa_circ_0007158, hsa_circ_0000375, hsa_circ_0018909 and hsa_circ_0011536) and 3 miRNAs (hsa-miR-601, hsa-miR-671-5p and hsa-miR-765), which could contain innovative and noninvasive indicators for the early screening and prognostic prediction of CRC. CONCLUSION We proposed a circRNA-miRNA-mRNA regulatory network closely associated with the progression and clinical outcome of CRC that might include promising biomarkers for carcinogenesis and therapeutic targets.

Circular RNA circFAT1(e2) Facilitates Cell Progression through the miR-30e-5P/MYBL2 Pathway in Glioma

“…The circRNA-miRNA-mRNA regulatory network is the main mechanism that can influence cancer-related gene expression [ 7 ]. The main function of circRNA is as a sponge of miRNAs in this network [ 8 ].…”

Identification of circ_0000375 and circ_0011536 as novel diagnostic biomarkers of colorectal cancer

“…The circRNAs differentially expressed between CRC and NC were obtained with the criteria |log2 fold change| > 1 and P value < 0.05 (Figure 1A ). Based on the circRNA regulatory network identified in our previous study[ 20 ], we selected 2 circRNAs, namely, hsa_circ_0000375 (circ_0000375) and hsa_circ_0011536 (circ_0011536), which were downregulated in CRC (Figure 1B and C ). The AUCs of circ_0000375 and circ_0011536 were 0.970 and 0.920, respectively (Figure 1D ), suggesting that these 2 circRNAs were useful as CRC biomarkers in the GSE126095 dataset.…”

Microarray Identifies a Key Carcinogenic Circular RNA 0008594 That Is Related to Non-Small-Cell Lung Cancer Development and Lymph Node Metastasis and Promotes NSCLC Progression by Regulating the miR-760-Mediated PI3K/AKT and MEK/ERK Pathways

“…Since the introduction of circRNA in cancer research and the progress of genetic detection technology (such as microarray and RNA sequencing), an increasing number of studies have been conducted to investigate the underlying role of the circRNA profile in cancers, including lung cancer (20,(33)(34)(35)(36). A previous study identified five upregulated circRNAs and 30 downregulated circRNAs in small-cell-lung cancer (SCLC) tissues compared to adjacent non-cancerous tissues using nextgeneration sequencing (37).…”