A meta-analysis and bioinformatics exploration of the diagnostic value and molecular mechanism of miR-193a-5p in lung cancer

Abstract

Lung cancer is a leading cause of mortality worldwide and despite recent improvements in lung cancer treatments patient mortality remains high. miR-193a-5p serves a crucial role in the initiation and development of cancer; it is necessary to understand the underlying molecular mechanisms of miR-193a-5p in lung cancer, which may enable the development of improved clinical diagnoses and therapies. The present study investigated the diagnostic value of peripheral blood and tissue miR-193a-5p expression using a microarray meta-analysis. Peripheral blood miR-193a-5p was revealed to be upregulated in patients with lung cancer. The pooled area under the curve (AUC) was 0.67, with a sensitivity and specificity of 0.74 and 0.56, respectively. Conversely, the peripheral tissue miR-193a-5p expression in patients with lung cancer was significantly downregulated. The pooled AUC was 0.83, and the sensitivity and specificity were 0.65 and 0.89, respectively. Through bioinformatics analysis, three Kyoto Encyclopedia of Genes and Genomes (KEGG) terms, pathways in cancer, prostate cancer and RIG-I-like receptor signaling pathway, were identified as associated with miR-193a-5p in lung cancer. In addition, in lung cancer, six key miR-193a-5p target genes, receptor tyrosine-protein kinase erbB-2 (ERBB2), nuclear cap-binding protein subunit 2 (NCBP2), collagen α-1(I) chain (COL1A1), roprotein convertase subtilisin/kexin type 9 (PCSK9), casein kinase II subunit α (CSNK2A1) and nucleolar transcription factor 1 (UBTF), were identified, five of which were significantly upregulated (ERBB2, NCBP2, COL1A1, CSNK2A1 and UBTF). The protein expression of ERBB2, NCBP2, COL1A1, CSNK2A1 and UBTF was also upregulated. NCBP2 and CSNK2A1 were negatively correlated with miR-193a-5p. The results demonstrated that miR-193a-5p exhibited opposite expression patterns in peripheral blood and tissue. Upregulated peripheral blood miR-193a-5p and downregulated tissue miR-193a-5p may be promising diagnostic biomarkers in lung cancer. In addition, the KEGG terms pathways in cancer, prostate cancer and RIG-I-like receptor signaling pathway may suggest which pathways serve vital roles in lung cancer by regulating miR-193a-5p. In addition, six genes, ERBB2, COL1A1, PCSK9, UBTF and particularly NCBP2 and CSNK2A1, may be key target genes of miR-193a-5p in lung cancer.

Keywords: bioinformatics; diagnosis; lung cancer; microRNA-193a-5p; target genes.

Figure 1.

Meta-analysis evaluating the diagnostic value of peripheral blood miR-193a-5p. (A) Forest plot determining the differences in peripheral blood miR-193a-5p expression. (B) Funnel plot determining the publication bias of the included peripheral blood datasets. miR, microRNA; SMD, standard mean difference.

Figure 2.

Diagnostic SROC curve of miR-193a-5p in lung cancer. The X-axis represents the specificity, and the Y-axis represents the sensitivity. Each red dot with a number inside represents each included dataset. The green diamond represents the summary operating point. (A) SROC curve of the peripheral blood miR-193a-5p. (B) SROC curve of the tissue miR-193a-5p. SROC, summary receiver operating characteristic; miR, microRNA; SENS, sensitivity; SPEC, specificity; AUC, area under the curve.

Figure 3.

Forest plots evaluating the diagnostic sensitivity, specificity and odds ratio (OR) of peripheral blood miR-193a-5p. (A) Pooled sensitivity and specificity of peripheral blood miR-193a-5p. (B) Pooled diagnostic OR of peripheral blood miR-193a-5p. OR, odds ratio; miR, microRNA.

Figure 4.

Forest plots evaluating the pooled positive and negative likelihood ratios (LRs) of peripheral blood miR-193a-5p expression. (A) Pooled positive LR of peripheral blood miR-193a-5p. (B) Pooled negative LR peripheral blood miR-193a-5p. LR, likelihood ratio; miR, microRNA.

Figure 5.

Meta-analysis evaluating the diagnostic value of tissue miR-193a-5p. (A) Forest plot determining the differences in tissue miR-193a-5p. (B) Funnel plot determining the publication bias of the included tissue datasets. miR, microRNA; SMD, standard mean difference.

Figure 6.

Forest plots evaluating the diagnostic sensitivity, specificity and odds ratio (OR) of tissue miR-193a-5p. (A) Pooled sensitivity and specificity of tissue miR-193a-5p. (B) Pooled diagnostic OR of tissue miR-193a-5p. OR, odds ratio; miR, microRNA.

Figure 7.

Forest plots evaluating the pooled positive and negative likelihood ratios (LRs) of tissue miR-193a-5p. (A) Pooled positive LR of tissue miR-193a-5p. (B) Pooled negative LR tissue miR-193a-5p. LR, likelihood ratio; miR, microRNA.

Figure 8.

Significantly enriched GO and KEGG terms for the 81 overlapping genes. The X-axis represents the number of genes, and the Y-axis represents different terms. (A) The significantly enriched BP terms. (B) The significantly enriched CC terms. (C) The significantly enriched molecular function (MF) terms. (D) The significantly enriched KEGG terms. BP, biological process; CC, cellular component. GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; BP, biological process; CC, cellular component; MF, molecular function.

Figure 8.

Significantly enriched GO and KEGG terms for the 81 overlapping genes. The X-axis represents the number of genes, and the Y-axis represents different terms. (A) The significantly enriched BP terms. (B) The significantly enriched CC terms. (C) The significantly enriched molecular function (MF) terms. (D) The significantly enriched KEGG terms. BP, biological process; CC, cellular component. GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; BP, biological process; CC, cellular component; MF, molecular function.

Figure 9.

Protein-protein interaction network of the overlapping genes. Each node represents a protein. Filled nodes indicate that 3D structure of the protein is known or predicted. Empty nodes indicate that the 3D structure of the protein has not been determined. The edges among the nodes represent the protein associations. The edge thickness indicates the confidence level. PPI, protein-protein interaction.

Figure 10.

The expression scatter plots and ROC curves of the five upregulated hub genes. (A) The expression of ERBB2 in lung cancer and normal tissues. (B) The ROC curve of ERBB2 to assess the diagnostic value. (C) The expression of NCBP2 in lung cancer and normal tissues. (D) The ROC curve of NCBP2 to assess the diagnostic value. (E) The expression of COL1A1 in lung cancer and normal tissues. (F) The ROC curve of COL1A1 to assess the diagnostic value. (G) The expression of CSKN2A1 in lung cancer and normal tissues. (H) The ROC curve of CSKN2A1 to assess the diagnostic value. (I) The expression of UBTF in lung cancer and normal tissues. (J) The ROC curve of UBTF in lung cancer and normal tissues. ROC, receiver operating characteristic; AUC, area under the curve.

Figure 11.

The expression scatter plots and ROC curve of the downregulated hub gene. (A) The expression of PCKS9 in lung cancer and normal tissues. (B) The ROC curve of PCKS9 in lung cancer and normal tissues. ROC, receiver operating characteristic; AUC, area under the curve.

Figure 12.

The protein expression of the hub genes based on The Human Protein Atlas database (https://www.proteinatlas.org/). Brown staining indicates protein expression. Darker staining indicates higher protein expression. (A) Medium staining of ERBB2 in LUAD (stained with the antibody HPA001383). (B) High staining of NCBP2 in LUAD (stained with the antibody HPA044850). (C) Medium staining of COL1A1 in LUAD (stained with the antibody HPA011795). (D) Medium staining of CSNK2A1 in LUAD (stained with the antibody CAB069395). (E) High staining of UBTF in LUAD (stained with the antibody CAB004611). (F) Medium staining of ERBB2 in LUSC (stained with the antibody HPA001383). (G) High staining of NCBP2 in LUSC (stained with the antibody HPA044850). (H) Medium staining of COL1A1 in LUSC (stained with the antibody HPA011795). (I) High staining of CSNK2A1 in LUSC (stained with the antibody CAB069395). (J) High staining of UBTF in LUSC (stained with the antibody CAB004611). Magnification, ×40. LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma.

Figure 13.

The correlation between miR-193a-5p and hub genes. Each plot represents a lung cancer sample. The X-axis represents the expression of miR-193a-5p. The Y-axis represents the expression of hub genes. (A) miR-193a-5p is negatively correlated with NCBP2. (B) miR-193a-5p is negatively correlated with CSNK2A1. miR, microRNA.