Abstract
BackgroundThe underlying circular RNAs (circRNAs)-related competitive endogenous RNA (ceRNA) mechanisms of pathogenesis and prognosis in non-small cell lung cancer (NSCLC) remain unclear.MethodsDifferentially expressed circRNAs (DECs) in two Gene Expression Omnibus datasets (GSE101684 and GSE112214) were identified by utilizing R package (Limma). Circinteractome and StarBase databases were used to predict circRNA associated-miRNAs and mRNAs, respectively. Then, protein–protein interaction (PPI) network of hub genes and ceRNA network were constructed by STRING and Cytoscape. Also, analyses of functional enrichment, genomic mutation and diagnostic ROC were performed. TIMER database was used to analyze the association between immune infiltration and target genes. Kaplan–Meier analysis, cox regression and the nomogram prediction model were used to evaluate the prognostic value of target genes. Finally, the expression of potential circRNAs and target genes was validated in cell lines and tissues by quantitative real-time PCR (qRT-PCR) and Human Protein Atlas (HPA) database.ResultsIn this study, 15 DECs were identified between NSCLC tissues and adjacent-normal tissues in two GEO datasets. Following the qRT-PCR corroboration, 7 DECs (hsa_circ_0002017, hsa_circ_0069244, hsa_circ_026337, hsa_circ_0002346, hsa_circ_0007386, hsa_circ_0008234, hsa_circ_0006857) were dramatically downregulated in A549 and SK-MES-1 compared with HFL-1 cells. Then, 12 circRNA-sponged miRNAs were screened by Circinteractome and StarBase, especially, hsa-miR-767-3p and hsa-miR-767-5p were significantly up-regulated and relevant to the prognosis. Utilizing the miRDB and Cytoscape, 12 miRNA-target genes were found. Functional enrichment, genomic mutation and diagnostic analyses were also performed. Among them, FNBP1, AKT3, HERC1, COL4A1, TOLLIP, ARRB1, FZD4 and PIK3R1 were related to the immune infiltration via TIMER database. The expression of ARRB1, FNBP1, FZD4, and HERC1 was correlated with poor overall survival (OS) in NSCLC patients by cox regression and nomogram. Furthermore, the hub-mRNAs were validated in cell lines and tissues.ConclusionWe constructed the circRNA-miRNA-mRNA network that might provide novel insights into the pathogenesis of NSCLC and reveal promising immune infiltration and prognostic biomarkers.
Highlights
Lung cancer is one of the most frequent diagnosed cancer and has the highest rate of mortality [1]
Differential expression analysis for circular RNA (circRNA) In order to identify the potential circRNAs related to progression and carcinogenesis of non-small cell lung cancer (NSCLC), differential expression analysis was performed between NSCLC tissues and adjacent-normal lung tissues on two selected Gene Expression Omnibus (GEO) datasets
Prediction and analysis of circRNAs‐targeted miRNAs Studies have shown that in the competitive endogenous RNA (ceRNA) network, circRNA can act as a miRNA sponge to regulate gene expression
Summary
Lung cancer is one of the most frequent diagnosed cancer and has the highest rate of mortality [1]. Accumulating evidences have indicated that circular RNA (circRNA), a new class of endogenous RNA with covalent loop and formed by reverse splicing of precursor mRNA [4], served as key role to regulate the target genes’ expression [5,6,7]. As far as NSCLC is concerned, hsa-circRNA-002178 was found to be upregulated and could act as a ceRNA via sponging miR-34 to induce PD1 expression in LUAD [13]. Understanding of the pivotal circRNA-miRNA-mRNA ceRNA networks associated significantly with carcinogenesis and progression of NSCLC remain very limited, and novel therapeutic indicators and prognostic markers require further explored. The underlying circular RNAs (circRNAs)-related competitive endogenous RNA (ceRNA) mechanisms of pathogenesis and prognosis in non-small cell lung cancer (NSCLC) remain unclear
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