Open Access

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

  • Authors:
    • Zu‑Cheng Xie
    • Rui‑Xue Tang
    • Xiang Gao
    • Qiong‑Ni Xie
    • Jia‑Ying Lin
    • Gang Chen
    • Zu‑Yun Li
  • View Affiliations

  • Published online on: July 19, 2018     https://doi.org/10.3892/ol.2018.9174
  • Pages: 4114-4128
  • Copyright: © Xie et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

Introduction

Lung cancer ranks second in incidence and first in mortality for both males and females, with an estimated 222,500 new cases and 155,870 deaths in 2017 (1). Unfortunately, the majority of lung cancer patients are diagnosed at an advanced stage and are typically not curable. The current gold standard for lung cancer diagnosis is pathological biopsy, which is an invasive method. With the development of nondestructive testing technology, novel non-invasive methods are needed to monitor and diagnose lung cancer. Though some findings regarding molecular mechanisms in lung cancer have been reported in recent years (26), the molecular regulatory mechanisms underlying the initiation and development of lung cancer remain unclear. Therefore, more studies are needed to explore the molecular mechanisms in lung cancer.

MicroRNAs (miRNAs) are highly conserved endogenous small non-coding RNAs approximately 23 nucleotides in length. They exert their effects through posttranscriptional repression in a sequence-specific manner (7). miRNAs have been found to perform crucial biological functions in the initiation and development of cancer (8). In addition, miRNAs have begun to be used for the diagnosis and treatment of cancer in recent years (911). The clinical significance of miRNA profiles in diagnosis and prognosis has also been evaluated in lung cancer (12,13).

Over the past few years, miR-193a-5p has been found to be involved in multiple cancers, such as esophageal squamous cell carcinoma (14), bladder cancer (15), primary bone tumors (16), osteosarcoma (17), colorectal cancer (18) and endometrioid endometrial adenocarcinoma (19). Some noted pathways such as the PI3K/AKT signaling pathway, PTEN/AKT signaling pathway and mTOR signaling pathway have been implicated in the oncogenesis of different tumors and as therapeutic drug targets (2024). Some studies have linked miR-193a-5p to lung cancer. For example, in Yu's study, miR-193a-5p was found to block the metastasis of non-small cell lung cancer by inhibiting the ERBB4/PIK3R3/mTOR/S6K2 signaling pathway (25). Similarly, Chen et al (26)revealed that the miR-193a-5p-WT1-E-cadherin axis plays a crucial role in the metastasis of non-small cell lung cancer. However, no study has reported the diagnostic value of miR-193a-5p in lung cancer.

Thus, we attempted to explore the clinical diagnostic significance of miR-193a-5p using a microarray meta-analysis. We also explored the possible molecular mechanisms using bioinformatics analysis. The results of this study could provide insights into the clinical diagnosis of lung cancer and guide future research on the underlying molecular mechanisms.

Materials and methods

GEO dataset retrieval and data extraction

Lung cancer microarray data published through July 2017 were retrieved from the Gene Expression Omnibus (GEO) database. The retrieval strategies were as follows: (lung OR pulmonary OR respiratory OR bronchi OR bronchioles OR alveoli OR pneumocytes OR ‘air way’) and (cancer OR carcinoma OR tumor OR neoplas* OR malignan* OR adenocarcinoma) and (MicroRNA OR miRNA OR ‘Micro RNA’ OR ‘Small Temporal RNA’ OR ‘non-coding RNA’ OR ncRNA OR ‘small RNA’). Microarray data meeting the following criteria were included: i) The subjects in the datasets included lung cancer patients and corresponding controls; ii) the expression profile of miR-193a-5p in both lung cancer patients and controls was available or calculable; and iii) the number of overall subjects was more than 30. The expression of miR-193a-5p was extracted from the included datasets and evaluated with means and standard deviations (SD) using SPSS 22.0 (SPSS, Inc., Chicago, IL, USA).

Meta-analysis of the diagnostic value of miR-193a-5p in the GEO datasets

A meta-analysis of the included datasets was conducted to evaluate the diagnostic value of miR-193a-5p using Stata 12.0 software (StataCorp LP, College Station, TX, USA). The pooled effect was estimated as the standard mean difference (SMD) with a 95% confidence interval (CI). The heterogeneity was measured using a chi-squared test of Q and P values. I2<50% or P>0.05 indicated no significant heterogeneity. The publication bias of the datasets was assessed using Begg's funnel plots. A symmetrical funnel plot indicated no obvious publication bias. In addition, summary receiver operating characteristic (SROC) analysis was performed. The pooled diagnostic sensitivity, specificity, odds ratio (OR), positive likelihood ratio (LR) and negative LR were calculated to comprehensively evaluate the diagnostic value of miR-193a-5p.

Identification of miR-193a-5p target genes

Possible target genes of miR-193a-5p were collected using miRWalk 2.0 (http://zmf.umm.uni-heidelberg.de/mirwalk2) (27), which combines 12 prediction databases. Genes predicted by at least 2 databases were selected. We also identified validated target genes of miR-193a-5p using the Tarbase and MitarBase databases. The predicted genes and validated genes were further compared to identify the most significant overlapping miR-193a-5p target genes.

Exploration of the molecular mechanism of miR-193a-5p using bioinformatics analysis

The Database for Annotation, Visualization and Integrated Discovery (DAVID), an online bioinformatics functional enrichment tool for the analysis of large lists of genes (28,29), was used to explore the enriched pathways of the overlapping genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the DAVID online functional annotation module. Furthermore, to identify hub genes, we used the STRING v10 database (http://string-db.org/) (30) to construct a protein-protein interaction (PPI) network. Genes with connection degrees higher than 3 were considered hub genes.

Validation of hub gene expression using TCGA data

The Cancer Genome Atlas (TCGA) (http://cancergenome.nih.gov) database is one of the largest publicly funded project platforms, providing information regarding cancer-causing genome alterations for more than 30 cancer types (31). To validate the expression of the hub genes, we downloaded the RNA-sequencing data of lung cancer and non-cancerous tissues from the TCGA database. The hub gene expression data in lung cancer and non-cancerous tissues were extracted. The expression values were normalized by log2 transformation and imported into GraphPad Prism 7.0 (GraphPad Software, Inc., La Jolla, CA, USA). Unpaired Student's t-test and receiver operating characteristic (ROC) curve analyses were conducted to assess the expression differences and clinical significance. Scatter plots were constructed to visualize the differences in miR-193a-5p expression between lung cancer and non-cancerous tissues. In addition, the area under the curve (AUC) was calculated to evaluate the diagnostic capability of miR-193a-5p. A P-value <0.05 was considered statistically significant.

Validation of the protein expression of the hub genes

The Human Protein Atlas database (https://www.proteinatlas.org/) provides abundant proteome and transcriptome data for tissues, cells and cancers (3234). The protein expression of the upregulated hub genes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) specimens was investigated using the Pathology Altas portal in The Human Protein Atlas database. Antibody staining was analyzed to reflect the protein expression, and only samples with a staining quality of over 75% were used. Pathological images of typical high/medium staining in LUSC cells were chosen for display in this study.

Validation of the correlation analysis between miR-193a-5p and hub genes based on TCGA data

The expression data of miR-193a-5p and the six hub genes in lung cancer were downloaded from the TCGA database. The expression data of both miR-193a-5p and the hub genes were normalized by log2 transformation. Spearman's correlation analysis was further performed using GraphPad Prism 7.0 (GraphPad Software, Inc.). A Spearman correlation coefficient of r<0 indicated a negative correlation between miR-193a-5p and its hub genes. P<0.05 indicated the statistical significance of the correlation analysis.

Results

Overview of the included datasets

According to the retrieval criteria, a total of 15 datasets published from 2009 to 2016 were selected, including 7 peripheral blood datasets and 8 tissue datasets. The basic information of the included datasets is provided in Table I (3549). In the 7 peripheral blood datasets, 453 lung cancer samples and 306 healthy controls were included. In the 8 tissue datasets, 693 lung cancer samples and 354 healthy controls were included. The miR-193a-5p expression data were normalized by log2 transformation and extracted as the mean and SD.

Table I.

Characteristics of the GEO datasets included in the meta-analysis.

Table I.

Characteristics of the GEO datasets included in the meta-analysis.

Study informationSampleArray and annotation information



AuthorPublication yearCountrySample sourceData sourceLung cancer patientsHealthy controlsPlatformRefs.
Keller et al2009GermanyPeripheral bloodGSE176811719GPL9040(35)
Patnaik et al2011USAPeripheral bloodGSE274862232GPL11432(36)
Keller et al2011GermanyPeripheral bloodGSE315683267GPL9040(37)
Patnaik et al2012USAPeripheral bloodGSE407388258GPL16016(38)
Keller et al2014GermanyPeripheral bloodGSE617417394GPL9040(39)
Godrey et al2014USAPeripheral bloodGSE467292424GPL8786(40)
Leidinger et al2015GermanyPeripheral bloodGSE6895120312GPL16770(41)
Tan et al2010ChinaSCLC/NSCLCGSE15008182185GPL8176(42)
Nymark et al2011FinlandNSCLCGSE255082626GPL7731(43)
Ohba et al2013JapanNSCLC/SCLCGSE19945558GPL9948(44)
Bjaanaes et al2014NorwayLUADGSE4841415420GPL16770(45)
Robles et al2015USALUADGSE638053230GPL18410(46)
Gasparini et al2015SwitzerlandNSCLCGSE725266718GPL20275(47)
Jin et al2015ChinaSCLC/LUAD/LUSCGSE741909244GPL19622(48)
Yoshimoto et al2016JapanSCLC/LUADGSE773808523GPL16770(49)

[i] NSCLC, non-small cell lung cancer; SCLC, small cell lung cancer.

Meta-analysis of the diagnostic value of peripheral blood miR-193a-5p

The expression of peripheral blood miR-193-5p in the 7 independent peripheral blood datasets was pooled in a forest plot (Fig. 1A). The SMD was 0.29 (95% CI: 0.02 to 0.55; I2=56.0%; P=0.034). The SMD was pooled using a random-effects model since heterogeneity was observed (I2>50% or P-value <0.05). Publication bias was analyzed with a Begg's funnel plot (Fig. 1B). The Begg's funnel plot was basically symmetrical, indicating that no significant publication bias existed among the 7 peripheral blood datasets. SROC analysis was carried out to further examine the diagnostic value of peripheral blood miR-193a-5p. As shown in Fig. 2, the AUC was 0.67 with a 95% CI of 0.63 to 0.71. As shown in Fig. 3A, the combined sensitivity was 0.74 (95% CI: 0.57 to 0.86; I2=84.56%; P=0.00), while the specificity was 0.56 (95% CI: 0.44 to 0.67; I2=68.08%; P=0.00). Fig. 3B shows that the pooled diagnostic odds ratio (OR) was 3.21 (95% CI: 2.00 to 5.15). The pooled positive LR and negative LR were also calculated to evaluate the association between miR-193a-5p and lung cancer (Fig. 4A and B). The pooled positive LR was 1.58 (95% CI: 1.35 to 1.85), while the negative LR was 0.57 (95% CI: 0.47 to 0.70).

Meta-analysis of the diagnostic value of tissue miR-193-5p

As shown in Fig. 5A, eight tissue datasets were pooled using a random-effects model, and the pooled SMD was −0.34 (95% CI: −0.59 to −0.08; I2=63.2%; P=0.008). A Begg's funnel plot was constructed, and no publication bias was found, as the funnel plot was symmetrical (Fig. 5B). In addition, SROC curve analysis showed satisfactory diagnostic value of tissue miR-193-5p, with an AUC of 0.83 (95% CI: 0.79 to 0.86) (Fig. 2B). The combined sensitivity and specificity was 0.65 (95% CI: 0.43–0.83) and 0.89 (95% CI: 0.58 to 0.98), respectively (Fig. 6A). However, significant heterogeneity was found (I2>50%; P<0.05). The combined diagnostic OR was 5.08 (95% CI: 2.17 to 11.89), which was calculated using a random-effects model due to the heterogeneity (Fig. 6B). Moreover, the pooled positive LR and negative LR was 2.15 (95% CI: 1.27 to 3.64) and 0.57 (95% CI: 0.42 to 0.77), respectively (Fig. 7A and B).

Identification of miR-193a-5p targets

A total of 12666 predicted target genes were obtained from miRWalk 2.0. Meanwhile, 94 validated target genes were collected from miRTarbase and Tarbase. Eighty-one overlapping genes were identified by comparing the predicted and validated target genes. The 81 overlapping genes are important miR-193a-5p target genes and were used for further bioinformatics analysis.

Bioinformatics analysis of the overlapping genes

GO, KEGG and PPI bioinformatics analyses were carried out for the overlapping genes (Table II). As shown in Fig. 8A, in biological process (BP), the top three enriched items were regulation of neuron apoptosis, negative regulation of kinase activity and skin development. In cellular component (CC), organelle outer membrane, mitochondrial outer membrane and fibrillar collagen were the top three enriched terms (Fig. 8B). For molecular function (MF), the target genes were mainly enriched in tubulin-tyrosine ligase activity, protein dimerization activity and platelet-derived growth factor binding (Fig. 8C). KEGG analysis showed that the significant terms associated with miR-193a-5p in lung cancer were pathway in cancer, prostate cancer and RIG-I-like receptor signaling pathway (Fig. 8D). By constructing a PPI network (Fig. 9), we identified 6 hub genes with a connection degree >3 (ERBB2, NCBP2, COL1A1, PCSK9, CSNK2A1, and UBTF). These 6 hub genes were the most densely connected areas in the network and were supported by additional evidence based on known interactions. These genes were more likely to be functionally connected, thus showing great potential to be key target genes of miR-193a-5p in lung cancer.

Table II.

The significant GO and KEGG enriched terms of the 81 overlapping genes.

Table II.

The significant GO and KEGG enriched terms of the 81 overlapping genes.

CategoryIDTermCountP-valueGenes
GOTERM_BP_FATGO:0043408Regulation of MAPKKK cascade50.001553FGF19, ERBB2, IGF2, TIMP2, TP73
GOTERM_BP_FATGO:0001889Liver development40.001824CEBPA, ERBB2, CEBPG, PCSK9
GOTERM_BP_FATGO:0045765Regulation of angiogenesis40.002994ERBB2, RNH1, ERAP1, RUNX1
GOTERM_BP_FATGO:0044092Negative regulation of molecular function70.004164CEBPG, RGS4, PCSK9, IGF2, TP73, DHCR24, THY1
GOTERM_BP_FATGO:0010627Regulation of protein kinase cascade60.005595MAVS, FGF19, ERBB2, IGF2, TIMP2, TP73
GOTERM_BP_FATGO:0007243Protein kinase cascade70.006808ERBB2, RGS4, WNK1, DUSP10, MKNK2, IGF2, TANK
GOTERM_BP_FATGO:0006469Negative regulation of protein kinase activity40.007393RGS4, IGF2, TP73, THY1
GOTERM_BP_FATGO:0043588Skin development30.007749COL1A2, COL1A1, DHCR24
GOTERM_BP_FATGO:0033673Negative regulation of kinase activity40.008115RGS4, IGF2, TP73, THY1
GOTERM_BP_FATGO:0043523Regulation of neuron apoptosis40.008115CASP9, PCSK9, TP73, DHCR24
GOTERM_CC_FATGO:0005584Collagen type I20.008743COL1A2, COL1A1
GOTERM_CC_FATGO:0070013Intracellular organelle lumen150.018944CEBPA, NCBP2, PDCD11, CEBPG, TRIM25, IGF2, SENP5, RBBP6, CSNK2A1, UBTF, VCP, INTS4, ANXA11, CDK12, ERAP1
GOTERM_CC_FATGO:0031981Nuclear lumen130.021220NCBP2, CEBPA, PDCD11, CSNK2A1, UBTF, VCP, INTS4, CEBPG, ANXA11, CDK12, TRIM25, SENP5, RBBP6
GOTERM_CC_FATGO:0005783Endoplasmic reticulum100.022714GABARAPL1, CYP1B1, VCP, ACO1, NUP210, PCSK9, ERAP1, IGF2, DHCR24, THY1
GOTERM_CC_FATGO:0044421Extracellular region part100.022714HDGF, COL1A2, RNH1, PCSK9, IGF2, FSTL1, COL1A1, NRG1, TNFSF9, TIMP2
GOTERM_CC_FATGO:0043233Organelle lumen150.022719CEBPA, NCBP2, PDCD11, CEBPG, TRIM25, IGF2, SENP5, RBBP6, CSNK2A1, UBTF, VCP, INTS4, ANXA11, CDK12, ERAP1
GOTERM_CC_FATGO:0031974Membrane-enclosed lumen150.026486CEBPA, NCBP2, PDCD11, CEBPG, TRIM25, IGF2, SENP5, RBBP6, CSNK2A1, UBTF, VCP, INTS4, ANXA11, CDK12, ERAP1
GOTERM_CC_FATGO:0005583Fibrillar collagen20.051347COL1A2, COL1A1
GOTERM_CC_FATGO:0005741Mitochondrial outer membrane30.059102MAVS, TOMM70A, BCL2L11
GOTERM_CC_FATGO:0031968Organelle outer membrane30.076066MAVS, TOMM70A, BCL2L11
GOTERM_MF_FATGO:0008047Enzyme activator activity70.006987CASP9, RGS4, RANBP1, MYO9B, NRG1, TIMP2, THY1
GOTERM_MF_FATGO:0042802Identical protein binding90.015402CEBPA, ERBB2, COL1A2, CLDN1, PCSK9, TPRG1 L, MYO9B, COL1A1, RUNX1
GOTERM_MF_FATGO:0019838Growth factor binding40.016275ERBB2, COL1A2, IGF2, COL1A1
GOTERM_MF_FATGO:0043125ErbB-3 class receptor binding20.020182ERBB2, NRG1
GOTERM_MF_FATGO:0000339RNA cap binding20.039963NCBP2, EIF4G3
GOTERM_MF_FATGO:0008083Growth factor activity40.048576FGF19, HDGF, IGF2, NRG1
GOTERM_MF_FATGO:0048407Platelet-derived growth factor binding20.054540COL1A2, COL1A1
GOTERM_MF_FATGO:0046983Protein dimerization activity70.056783CEBPA, ERBB2, NUP210, CEBPG, NFE2L1, MYO9B, RUNX1
GOTERM_MF_FATGO:0,004835Tubulin-tyrosine ligase activity20.068899TTLL4, TTLL11
KEGG_PATHWAYhsa04622RIG-I-like receptor signaling pathway30.053910MAVS, TRIM25, TANK
KEGG_PATHWAYhsa05215Prostate cancer30.080182CASP9, ERBB2, IGF2
KEGG_PATHWAYhsa05200Pathways in cancer50.092374FGF19, CEBPA, CASP9, ERBB2, RUNX1

[i] GO, Gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.

Hub gene expression validation and clinical significance

The expression of the six hub genes (ERBB2, NCBP2, COL1A1, PCSK9, CSNK2A1, UBTF) is shown in scatter plots. ROC curves were also generated. We found that the expression of five of the hub genes (ERBB2, NCBP2, COL1A1, CSNK2A1, UBTF) were significantly upregulated in cancer. In addition, ROC curve analysis also showed that NCBP2, COL1A1, CSNK2A1 had satisfactory diagnostic value (Fig. 10). The AUC of ERBB2, NCBP2, COL1A1, CSNK2A1 and UBTF was 0.581, 0.898, 0.868, 0.899 and 0.723, respectively. However, the expression of PCSK9 was significantly downregulated in cancer, and the ROC curve analysis showed that its AUC was 0.899 (Fig. 11).

Protein expression of the upregulated hub genes

Antibody staining was performed (Fig. 12) and among the five upregulated hub genes, ERBB2, NCBP2, COL1A1, CSNK2A1 and UBTF, we discovered that the antibody staining of NCBP2 and UBTF was high (Fig. 12B and E), while that of ERBB2, COL1A1 and CSNK2A1 (Fig. 12A, C and D) was moderate in pathological LUAD sections. In pathological LUSC sections, the antibody staining of NCBP2, CSNK2A1 and UBTF was high (Fig. 12G, I and J), while that of ERBB2 and COL1A1 was moderate (Fig. 12F and H). The protein expression of ERBB2, NCBP2, COL1A1, CSNK2A1 and UBTF was upregulated in both LUAD and LUSC pathological sections. ERBB2 and COL1A1 were localized in the cytoplasm and cell membrane in both LUAD and LUSC pathological sections. CSNK2A1 and UBTF staining was predominantly nuclear in both LUAD and LUSC pathological sections. In LUAD sections, NCBP2 staining was both cytoplasmic/membranous and nuclear, while in LUSC sections, it was observed only in the nucleus.

Correlation between miR-193a-5p and hub genes

We analyzed a total of 1046 lung cancer samples from the TCGA database, including 533 LUAD and 513 LUSC samples. Among the five upregulated hub genes, we found that the expression of NCBP2 and CSNK2A1 was negatively correlated with that of miR-193a-5p (P<0.05). The correlation coefficient r was −0.154 (CI: −0.214 to −0.092) and −0.156 (CI: −0.216 to −0.094), respectively (Fig. 13). This finding further suggested that NCBP2 and CSNK2A1 are target genes of miR-193a-5p. However, there was no significant negative correlation between ERBB2, COL1A1 or UBTF and miR-193a-5p. Thus, based on our correlation analysis, we were unable to verify that ERBB2, COL1A1, and UBTF are miR-193a-5p target genes.

Discussion

In this study, we aimed to examine the diagnostic value of peripheral blood and tissue miR-193a-5p expression. We also attempted to elucidate the molecular regulatory mechanism underlying miR-193a-5p in lung cancer. We selected eligible microarray datasets and conducted a meta-analysis to explore the clinical diagnostic significance of miR-193a-5p. We then used bioinformatics analysis to explore the potential molecular mechanism involved. We compared predicted and validated target genes of miR-193a-5p and identified the overlapping genes. GO, KEGG and PPI network analyses were further performed for the overlapping genes. This study therefore provides a foundation for future research on miR-193a-5p.

Over the past few decades, the identification of diagnostic biomarkers in lung cancer has been an important research focus. Some classic and useful biomarkers such as TP53 (50,51), neuron-specific enolase (NSE) (52,53), carcinoembryonic antigen (CEA) (54,55), and the cytokeratin 19 fragment (CYFRA21-1) (56,57) have been identified and applied in clinical diagnosis. Nevertheless, there is still a need to identify diagnostic markers of lung cancer. Increasingly, lncRNAs and miRNAs have been found to act as diagnostic markers in lung cancer (5862). The combination of multiple diagnostic biomarkers would greatly improve the sensitivity and specificity of lung cancer diagnosis (56,63,64). Thus, each finding is likely to contribute to the future clinical diagnosis of lung cancer. No previous studies have elucidated the diagnostic value of miR-193a-5p through a comprehensive meta-analysis. In this study, we used a microarray meta-analysis to explore the diagnostic value of miR-193a-5p in lung cancer. We found that the expression of peripheral blood miR-193a-5p was significantly higher in lung cancer samples than in normal samples. The pooled AUC was 0.67, with a sensitivity of 0.74 and specificity of 0.56. The pooled diagnostic OR was 3.21, the positive likelihood ratio was 1.58 and the negative likelihood ratio was 0.57. Thus, peripheral blood miR-193a-5p displayed moderate diagnostic value. It may be useful to combine peripheral blood miR-193a-5p with other diagnostic markers to improve its clinical diagnostic efficacy. Surprisingly, in tissue samples, the expression of miR-193a-5p in lung cancer tissue was evidently reduced compared with normal tissue. The pooled AUC was 0.83, with a sensitivity of 0.65 and specificity of 0.89. The diagnostic OR was 5.08, the positive likelihood ratio was 2.15, and the negative likelihood ratio was 0.57. Thus, tissue miR-193a-5p expression exhibited satisfactory performance in diagnosing lung cancer and might be a promising clinical diagnostic biomarker. Interestingly, the expression of peripheral blood miR-193a-5p was not consistent with the expression observed in lung cancer tissue samples. The reasons for this discrepancy between peripheral blood and tissue miRNA expression remain unclear. The origin of peripheral blood miRNAs remains controversial. Some researchers have suggested that miRNAs are secreted through microvesicles/exosomes, and some miRNAs are expressed at a higher level in microvesicles than inside tumor cells (6567). In another study, Pigati et al (68) found that miRNAs were selectively released from malignant cells and that the level of miRNAs released did not necessarily reflect the original abundance of miRNAs in cells. In Hu's study, it was suggested that the clinical role of serum miRNAs was independent from that in tissue samples (69). These findings may indicate why the expression profiles of miR-193a-5p were opposite in peripheral blood and tissue specimens in our study. Further studies are needed to determine the exact mechanism that causes the difference in expression. Still, peripheral blood and tissue miR-193a-5p could facilitate the diagnosis of lung cancer to some extent.

Since miR-193a-5p exerts its regulatory effects by specifically targeting certain genes, we identified potential miR-193a-5p target genes and further uncovered the underlying regulatory pathways. We found that the top enriched GO terms in BP, CC and MF were regulation of neuron apoptosis, organelle outer membrane and tubulin-tyrosine ligase activity, respectively. Mitochondria are important organelles in most eukaryotes. Mitochondrial outer membrane permeabilization has been reported to be involved in cancer and may be a promising therapeutic target (70,71). Therefore, miR-193a-5p might also participate in lung cancer through a similar mechanism. Recently, widespread loss of tubulin tyrosine ligase has been found during tumor growth, suggesting that tubulin tyrosine ligase activity might be involved in the regulation of tumor cells (72). Tubulin tyrosine ligase activity may be associated with miR-193a-5p, which might exert effects in lung cancer. However, more studies are needed to confirm this. In our KEGG analysis, the terms pathways in cancer, prostate cancer and RIG-I-like receptor signaling pathway were determined to be important. However, no studies have yet determined the relationship between miR-193a-5p and these pathways. Thus, more studies are urgently required. Through PPI network construction, six hub genes were identified (ERBB2, NCBP2, COL1A1, PCSK9, CSNK2A1, UBTF). By analyzing TCGA data, we discovered that among the six hub genes, five (ERBB2, NCBP2, COL1A1, CSNK2A1, UBTF) were significantly upregulated in lung cancer tissue. Since the expression of miR-193a-5p in lung cancer tissue was downregulated, the five upregulated hub genes (ERBB2, NCBP2, COL1A1, CSNK2A1, UBTF) are likely to be target genes of miR-193a-5p in lung cancer. However, more studies are needed to investigate the relationship between the significantly downregulated hub gene, PCSK9, and miR-193a-5p in lung cancer. Interestingly, we further verified that the protein expression of ERBB2, NCBP2, COL1A1, CSNK2A1 and UBTF was also upregulated according to antibody staining in LUAD and LUSC pathological sections. These results further demonstrated the upregulation of ERBB2, NCBP2, COL1A1, CSNK2A1 and UBTF in lung cancer, indicating that they are likely to be targets of miR-193a-5p. Of the five upregulated hub genes, NCBP2 and CSNK2A1 were found to be negatively correlated with miR-193a-5p. Consequently, we focused on NCBP2 and CSNK2A1 in the detailed discussion below.

NCBP2 (nuclear cap binding protein subunit 2) is also known as CBC2. Its protein product is a component of the nuclear cap-binding protein complex. NCBP2 has been reported as a key target gene in ovarian carcinoma (73). However, we did not find any studies on NCBP2 and lung cancer. In our study, we found that the protein expression of NCBP2 was increased in both LUAD and LUSC samples. In addition, miR-193a-5p was found to be negatively correlated with NCBP2 (r=−0.154). These findings provided more evidence suggesting that NCBP2 may be a target of miR-193a-5p in lung cancer. Nevertheless, more relevant studies are required to further validate this hypothesis.

CSNK2A1 (casein kinase 2 alpha 1), also known as CKII, is a serine/threonine protein kinase that participates in various cellular processes, including the cell cycle, apoptosis, and circadian rhythm. Over the past few years, CSNK2A1 has been found to play a significant role in the survival of cancer patients, suggesting that it may be a promising therapeutic target (7476). For example, in Bae JS's study, CSNK2A1 was found to participate in the progression of breast carcinoma and to indicate poorer patient survival (77). In addition, Rabjerg et al (78) identified CSNK2A1 as a promising novel prognostic biomarker in clear cell renal carcinoma. Furthermore, CSNK2A1 has also been found to be involved in ovarian cancer (79), oral cancer (80), prostate cancer (81,82) and pancreatic cancer (83). A CK2 inhibitor has been implicated in the apoptosis, migration, and metastasis of lung cancer cells (8487). Increased protein expression of CSNK2A1 was observed in both LUAD and LUSC samples. We also observed a negative correlation between miR-193a-5p and CSNK2A1 according to an analysis of TCGA data (r=−0.156). Thus, CSNK2A1 could be a promising therapeutic target in lung cancer. Still, further experimental studies are needed.

In conclusion, in this study we discovered that peripheral blood and tissue miR-193a-5p could be a promising diagnostic biomarker for the clinical diagnosis of lung cancer. Several pathways regulated by miR-193a-5p and its targets, including pathways in cancer, prostate cancer and the RIG-I-like receptor signaling pathway, might be important in lung cancer. In addition, six hub genes, ERBB2, COL1A1, PCSK9, UBTF, and particularly NCBP2 and CSNK2A1, were identified as key target genes of miR-193a-5p. However, there were some limitations in this study. The analysis was based on online databases, and we only performed bioinformatics analyses. More experiments are needed to validate the findings. Luciferase assays would be a powerful method to validate the findings in the current study. Clinicall, this study could offer possible insights into lung cancer diagnosis and provide a basis for future research on the molecular mechanisms involved.

Acknowledgements

Not applicable.

Funding

The present study was supported the Fund of the Natural Science Foundation of Guangxi, China (grant no. 2016GXNSFAA380255) and Future Academic Star of Guangxi Medical University (grant no. WLXSZX17042). The funders were not involved in the study design, data collection and analysis, the decision to publish or preparation of the manuscript.

Availability of data and materials

All the data and materials used in the current study are freely accessible in GEO (https://www.ncbi.nlm.nih.gov/geo/), TCGA (https://cancergenome.nih.gov/), miRWalk 2.0 (http://zmf.umm.uni-heidelberg.de/apps/zmf/mirwalk2/), Tarbase (http://diana.imis.athena-innovation.gr/DianaTools/index.php?r=tarbase/index), MitarBase (http://mirtarbase.mbc.nctu.edu.tw/php/index.php), DAVID (https://david.ncifcrf.gov/), STRING (https://string-db.org/) and the Human Protein Atlas databases (https://www.proteinatlas.org/).

Authors' contributions

ZYL and GC designed the study and revised the manuscript. ZCX, RXT, XG, QNX, and JYL contributed to the collection and analysis of the data, as well as the writing of the manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

ERBB2

erb-b2 receptor tyrosine kinase 2

ERBB4

erb-b2 receptor tyrosine kinase 4

NCBP2

nuclear cap binding protein subunit 2

COL1A1

collagen type I alpha 1 chain

PCSK9

proprotein convertase subtilisin/kexin type 9

CSNK2A1

casein kinase 2 α1

UBTF

upstream binding transcription factor, RNA polymerase I

PIK3R3

phosphoinositide-3-kinase regulatory subunit

mTOR

mechanistic target of rapamycin kinase

S6K2

serine/threonine protein kinase 2

SROC

summary receiver operating characteristic

LR

likelihood ratio

DAVID

The Database for Annotation, Visualization and Integrated Discovery

GO

gene ontology

KEGG

Kyoto Encyclopedia of Genes and Genomes

PPI

protein-protein interaction

TCGA

The Cancer Genome Atlas

ROC

receiver operating characteristic

BP

biological process

CC

cellular component

MF

molecular function

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October-2018
Volume 16 Issue 4

Print ISSN: 1792-1074
Online ISSN:1792-1082

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Copy and paste a formatted citation
x
Spandidos Publications style
Xie ZC, Tang RX, Gao X, Xie QN, Lin JY, Chen G and Li ZY: A meta‑analysis and bioinformatics exploration of the diagnostic value and molecular mechanism of miR‑193a‑5p in lung cancer. Oncol Lett 16: 4114-4128, 2018
APA
Xie, Z., Tang, R., Gao, X., Xie, Q., Lin, J., Chen, G., & Li, Z. (2018). A meta‑analysis and bioinformatics exploration of the diagnostic value and molecular mechanism of miR‑193a‑5p in lung cancer. Oncology Letters, 16, 4114-4128. https://doi.org/10.3892/ol.2018.9174
MLA
Xie, Z., Tang, R., Gao, X., Xie, Q., Lin, J., Chen, G., Li, Z."A meta‑analysis and bioinformatics exploration of the diagnostic value and molecular mechanism of miR‑193a‑5p in lung cancer". Oncology Letters 16.4 (2018): 4114-4128.
Chicago
Xie, Z., Tang, R., Gao, X., Xie, Q., Lin, J., Chen, G., Li, Z."A meta‑analysis and bioinformatics exploration of the diagnostic value and molecular mechanism of miR‑193a‑5p in lung cancer". Oncology Letters 16, no. 4 (2018): 4114-4128. https://doi.org/10.3892/ol.2018.9174