Open Access

Integrated bioinformatic analysis of differentially expressed genes and signaling pathways in plaque psoriasis

  • Authors:
    • Yu‑Jing Zhang
    • Yu‑Zhe Sun
    • Xing‑Hua Gao
    • Rui‑Qun Qi
  • View Affiliations

  • Published online on: May 15, 2019     https://doi.org/10.3892/mmr.2019.10241
  • Pages: 225-235
  • Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Psoriasis is an immune‑mediated cutaneous disorder with a high incidence and prevalence. Patients with psoriasis may experience irritation, pain and psychological problems. The cause and underlying molecular etiology of psoriasis remains unknown. In an attempt to achieve a more comprehensive understanding of the molecular pathogenesis of psoriasis, the gene expression profiles of 175 pairs of lesional and corresponding non‑lesional skin samples were downloaded from 5 data sets in the Gene Expression Omnibus (GEO) database. Integrated differentially expressed genes (DEGs) were obtained with the use of R software. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were analyzed using the DAVID online analysis tool. The protein‑protein interaction (PPI) network was constructed on the STRING platform and hub genes were calculated with the use of Cytoscape software. Finally, GEO2R was used to determine the expression of the hub genes in scalp psoriasis. A total of 373 genes from the 5 data sets were identified as DEGs, including 277 upregulated and 96 downregulated genes. GO analysis revealed that immune responses and epidermal differentiation/development were the most enriched terms in biological processes, extracellular space/matrix was the most enriched term in cellular components, and endopeptidase inhibitor activity was the most enriched term in molecular functions. In the KEGG pathway enrichment, DEGs were mainly enriched in the metabolic and viral infection‑associated pathways. A total of 17 hub genes were calculated, including CSK2, CDC45, MCM10, SPC25, NDC80, NUF2, AURKA, CENPE, RRM2, DLGP5, HMMR, TTK, IFIT1, RSAD2, IFI6, IFI27 and ISG20, among which interferon‑α‑inducible genes were revealed to display a similar expression pattern as that obtained in scalp psoriasis. This comprehensive bioinformatic re‑analysis of GEO data provides new insights on the molecular pathogenesis of psoriasis and the identification of potential therapeutic targets for the treatment of psoriasis.

Introduction

Psoriasis, as characterized by a well-demarcated erythematous plaque with silver scales, is a chronic, immune-mediated disorder that mainly affects the skin and joints (1). The worldwide prevalence rates of psoriasis range from 0.9–8.5% in adults and 0–2.1% in children (2). Although this condition rarely poses a threat to life, the irritation, pain and especially the aberrant appearance make these patients susceptible to psychological problems, such as anxiety and depression (3,4). With recent advances in the understanding of psoriasis, an increasing number of therapies have emerged, however a high recurrence rate persists. Therefore, it is important to better understand the underlying molecular pathogenesis of psoriasis in order to identify more effective therapeutic approaches for the control of psoriasis development and progression.

Gene expression microarrays have been widely applied in psoriatic research and represent an important new tool for use in the identification of disease-related molecules associated with psoriasis. Recently, comprehensive analysis of microarray data from multiple centers has become a popular research area. Ainali et al investigated gene expression patterns in lesional and non-lesional psoriatic tissue samples from 2 GEO data sets to establish a molecular sub-groups within the clinical phenotype of plaque psoriasis (5). Mei and Mei screened differentially expressed genes based on 4 psoriatic data sets followed by characterization of gene functions and mutual interactions (6). Sevimoglu and Arga analyzed and integrated data from 12 studies to identify the potential candidates for disease biomarkers and therapeutic targets (7).

However, analysis of the unpaired data obtained from lesional and non-lesional samples may lead to a potential bias caused by disease heterogeneity. In order to eliminate or reduce such bias, only paired lesional and the corresponding non-lesional skin samples were selected and analyzed in this study. Information was compiled from 5 original microarray data sets, GSE14905 (8), GSE30999 (9,10), GSE34248 (11), GSE41662 (11) and GSE53552 (12), from the Gene Expression Omnibus (GEO) database. A total of 175 pairs of lesional and non-lesional skin samples from plaque psoriatic patients were selected. With use of bioinformatic methods, integrated differentially expressed genes (DEGs) were identified, followed by the Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Protein-protein interaction (PPI) analysis and hug gene calculation were subsequently performed. Finally, an additional GEO data set, GSE75343 (13), which contained a study of gene expression levels in scalp psoriatic patients, was used as a means to validate whether the hub genes obtained from the aforementioned databases exhibited a similar expression profile as that in scalp psoriatic lesions.

Through integration of the bioinformatic analyses of the gene expression from these 175 pairs of psoriatic skin samples, 377 genes were identified as DEGs, with 277 of these genes being upregulated and 96 genes downregulated. We revealed that these genes covered a wide range of biological functions in epidermal development, keratinization, immune responses, metabolic pathways, cell cycle and extracellular spaces. These results provide a comprehensive understanding of the molecular pathogenesis of the disease, which may guide subsequent studies on psoriasis research.

Materials and methods

Microarray data sets and data calibration

Using the keyword ‘psoriasis’, data sets using the descriptors ‘paired biopsy from both lesional and non-lesional skin’ and ‘pre-treatment status’ were screened. The raw files of 5 enrolled microarray data sets, including GSE14905 (8), GSE30999 (9,10), GSE34248 (11), GSE41662 (11) and GSE53552 (12) (Table I), were downloaded from the NCBI GEO database (https://www.ncbi.nlm.nih.gov/geo/). In each data set, only pre-treatment psoriatic skin samples and their matched adjacent normal samples were selected, which resulted in 175 pairs of skin samples from psoriatic patients for subsequent analysis. The raw files were processed with R software 3.5.1 (https://www.r-project.org) to convert the gene probe IDs to gene symbol codes. Finally, calibrations of gene expression levels according to the quartile method were performed for subsequent analysis.

Table I.

Information for psoriatic GEO data.

Table I.

Information for psoriatic GEO data.

GEO seriesPlatformSampleTypePair no.(Refs.)
GSE14905GPL570Paired LS and NLSPlaque psoriasis28Yao et al (8)
GSE30999GPL570Paired LS and NLSModerate to severe plaque psoriasis85Suárez-Fariñas et al (9)
GSE34248GPL570Paired LS and NLSMild to moderate plaque psoriasis14Bigler et al (11)
GSE41662GPL570Paired LS and NLSModerate to severe plaque psoriasis24Bigler et al (11)
GSE53552GPL570Paired LS and NLSModerate to severe plaque psoriasis24Russell et al (12)
GSE75343GPL570Paired scalp LS and scalp NLSModerate to severe plaque psoriasis with scalp involvement13Ruano et al (13)

[i] LS, lesional skin; NLS, non-lesional skin.

DEGs analysis and integration

A differential expression analysis on each GEO series, as based on paired-sample t-tests between psoriatic skin and adjacent normal skin samples, were performed with use of R software. A gene was defined as a differentially expressed gene between the psoriatic and normal sample when the P-value was <0.05 (P<0.05) and the gene expression fold change (FC) value was >2 or <0.5 (|log2FC|≥1), which were illustrated as Volcano plots. An overlap of total, upregulated or downregulated DEGs, plotted as Venn charts, from all 5 data sets were listed for subsequent function analysis.

GO term and KEGG pathway analysis of DEGs

The DAVID knowledgebase (https://david.ncifcrf.gov/), an online gene functional annotation tool, was used to analyze the function and pathway enrichment of candidate genes obtained (14). With this technique, the Fisher exact test P-value was calculated as a result of enrichment degree. The top 10 enrichment GO term or KEGG pathway annotations for both up- or downregulated DEGs obtained in our study were listed.

PPI network and hub gene analyses

The STRING platform, an online tool used for the structural and functional analysis of protein interactions (15), was used to identify interactions among proteins of interest. The corresponding results were analyzed and structured with the use of the Cytoscape software 3.6.1 (https://cytoscape.org). The hub genes, which were considered to be involved in playing pivotal regulatory roles in the PPI network, were subsequently calculated based on the overlapping results obtained by MCC (Maximal Clique Centrality) and DMNC (Density of Maximum Neighborhood Component) topological analysis methods, respectively, with use of the cytoHubba app built in the software (16).

GEO2R analysis of gene expression levels

The gene expression levels of hub genes were analyzed in GSE75343 (13), a microarray data set comparing gene expression levels of scalp psoriatic skin and adjacent normal skin samples (Table I). The GEO2R, an online analysis tool built in the GEO website, was used for this analysis. Statistical analyses were performed using paired-sample t-tests and a P-value <0.05 was required for results to be considered statistically significant. Scatter charts were plotted using GraphPad Prism 7.0 (GraphPad Software, Inc., La Jolla, CA, USA).

Results

Microarray data standardization and DEG identification in plaque psoriasis

With use of the quartile division method, gene expression levels of each of the 5 GEO series were standardized and the results of pre- and post-standardization are presented in Fig. 1A. After pre-processing of the data, DEGs were analyzed using paired-sample t-tests within each series using a screening criteria of P<0.05 and |log2FC|≥1 (Fig. 1B). The number of DEGs in each series, including up- and downregulated DEGs are presented in Table II. When DEGs in each series were intersected with one another, 373 genes, considered as integrated DEGs were obtained and used for subsequent analysis with 277 of these genes being upregulated and 96 downregulated (Fig. 2). The ratio of the number of upregulated genes to that of downregulated genes was close to 1:1 in each of the GEO data sets, however, in the integrated results this ratio was equal to approximately 3:1, indicating a possible commonality in the upregulated genes during psoriasis development while the downregulated genes differ in individuals.

Table II.

DEGs in each GEO series.

Table II.

DEGs in each GEO series.

GEO seriesNo. of total DEGsNo. of upregulated DEGsNo. of upregulated DEGs
GSE149051195682513
GSE3099919791040939
GSE342481670854816
GSE41662220310731130
GSE53552222010841136

[i] DEGs, differentially expressed genes.

GO and KEGG pathway enrichment analysis of DEGs

GO enrichment analysis, which is comprised of 3 functional groups (biological processes, cellular components and molecular functions), was performed using the DAVID online tool. Within each of the functional groups, the top 10 enrichment terms for both up- or downregulated DEGs as identified according to the Fisher's exact test P-value are listed in Tables III and IV. The corresponding visual diagrams are presented in Fig. 3A and B. Within the biological process function group, upregulated DEGs were mainly enriched in GO terms of immune responses, ectoderm development, defense responses, keratinization and epidermal development while downregulated DEGs were mainly enriched in the regulation of system processes, regulation of smooth muscle contraction and muscle organ development. Notably, with the exception of enrichment of the cornified envelope, which is an extremely tough structure formed beneath the cell membrane (17) in the upregulated DEGs group, both up- and downregulated DEGs were enriched in the extracellular space within the cellular component enrichment analysis. Within the molecular function enrichment group, the upregulated DEGs were mainly enriched in chemokine activity, chemokine receptor binding and endopeptidase inhibitor activity, while downregulated DEGs were enriched in cytoskeletal protein binding processes. The KEGG pathway enrichment was performed using the same analysis tool and the results, in which only the pathways for the upregulated genes are displayed by figure, due to the limited number of enrichment pathways in the downregulated group, are presented in Table V and Fig. 4. In upregulated DEGs, signaling pathways were mainly enriched in metabolic pathways, measles, influenza A and chemokine signaling pathways, while aldosterone-regulated sodium reabsorption and PPAR signaling pathways were enriched in downregulated DEGs.

Table III.

GO analysis of upregulated genes associated with psoriasis.

Table III.

GO analysis of upregulated genes associated with psoriasis.

TermCountRich factor (%)P-valueFunctional group
GO:0006955 immune response3916.049382724.38742E-13BP
GO:0007398 ectoderm development176.9958847742.50742E-08BP
GO:0006952 defense response2911.934156384.97398E-08BP
GO:0031424 keratinization93.7037037041.40384E-07BP
GO:0008544 epidermis development156.1728395063.81508E-07BP
GO:0009611 response to wounding2510.288065845.4487E-07BP
GO:0006954 inflammatory response187.4074074074.12036E-06BP
GO:0030855 epithelial cell differentiation124.9382716054.1551E-06BP
GO:0030216 keratinocyte differentiation93.7037037044.20155E-06BP
GO:0009913 epidermal cell differentiation93.7037037048.13933E-06BP
GO:0006935 chemotaxis124.9382716051.83209E-05BP
GO:0001533 cornified envelope62.4691358021.19845E-05CC
GO:0005576 extracellular region4920.164609050.000143627CC
GO:0005615 extracellular space239.4650205760.000294727CC
GO:0031262 Ndc80 complex31.2345679010.001187266CC
GO:0044421 extracellular region part2510.288065840.004874319CC
GO:0005792 microsome104.1152263370.00688315CC
GO:0042598 vesicular fraction104.1152263370.008255849CC
GO:0001772 immunological synapse31.2345679010.008416898CC
GO:0000777 condensed chromosome kinetochore52.0576131690.009278963CC
GO:0000793 condensed chromosome72.8806584360.010321628CC
GO:0008009 chemokine activity72.8806584363.62741E-05MF
GO:0004867 serine-type endopeptidase inhibitor activity93.7037037043.72441E-05MF
GO:0042379 chemokine receptor binding72.8806584365.23427E-05MF
GO:0004866 endopeptidase inhibitor activity104.1152263370.000171511MF
GO:0030414 peptidase inhibitor activity104.1152263370.00025684MF
GO:0004252 serine-type endopeptidase activity93.7037037040.001273205MF
GO:0008236 serine-type peptidase activity93.7037037040.003155874MF
GO:0017171 serine hydrolase activity93.7037037040.003376462MF
GO:0005125 cytokine activity93.7037037040.005452577MF
GO:0004175 endopeptidase activity135.3497942390.005566809MF

[i] GO, gene ontology; BP, biological process; CC, cellular component; MF, molecular function.

Table IV.

GO analysis of downregulated genes associated with psoriasis.

Table IV.

GO analysis of downregulated genes associated with psoriasis.

TermCountRich factor (%)P-valueFunctional group
GO:0044057 regulation of system process66.9767440.008882BP
GO:0006940 regulation of smooth muscle contraction33.4883720.010755BP
GO:0007517 muscle organ development55.8139530.011225BP
GO:0030003 cellular cation homeostasis55.8139530.020798BP
GO:0051241 negative regulation of multicellular organismal process44.6511630.030364BP
GO:0055080 cation homeostasis55.8139530.03044BP
GO:0042698 ovulation cycle33.4883720.031344BP
GO:0006937 regulation of muscle contraction33.4883720.035764BP
GO:0019432 triglyceride biosynthetic process22.3255810.036656BP
GO:0008016 regulation of heart contraction33.4883720.040411BP
GO:0005576 extracellular region2529.069770.00021CC
GO:0005615 extracellular space1213.953490.001648CC
GO:0044421 extracellular region part1416.279070.002814CC
GO:0031012 extracellular matrix66.9767440.047088CC
GO:0008092 cytoskeletal protein binding89.3023260.009079MF
GO:0003779 actin binding66.9767440.018296MF
GO:0004857 enzyme inhibitor activity55.8139530.037901MF
GO:0003995 acyl-CoA dehydrogenase activity22.3255810.068241MF
GO:0042803 protein homodimerization activity55.8139530.07167MF
GO:0008201 heparin binding33.4883720.084388MF
GO:0030246 carbohydrate binding55.8139530.084603MF

[i] GO, gene ontology; BP, biological process; CC, cellular component; MF, molecular function.

Table V.

KEGG analysis of DEGs associated with psoriasis.

Table V.

KEGG analysis of DEGs associated with psoriasis.

RegulationIDTermCountRich factor (%)P-valueGenes
Upregulatedhsa05164Influenza A114.2801556420.00022787IRF7, OAS3, CXCL8, IL1B, RSAD2, OAS1, OAS2, MX1, STAT1, TMPRSS4, CXCL10
Upregulatedhsa05162Measles93.5019455250.00073285CCNE1, PRKCQ, IRF7, OAS3, IL1B, OAS1, OAS2, MX1, STAT1
Upregulatedhsa04062Chemokine signaling pathway103.8910505840.00162187CXCL1, CCL22, CCL20, CXCL13, CXCL9, CXCL8, CXCR2, STAT1, CCL18, CXCL10
Upregulatedhsa05160Hepatitis C72.7237354090.01355117IFIT1, IRF7, OAS3, CXCL8, OAS1, OAS2, STAT1
Upregulatedhsa05168Herpes simplex infection83.1128404670.01820027CDK1, IFIT1, IRF7, OAS3, IL1B, OAS1, OAS2, STAT1
Upregulatedhsa00240Pyrimidine metabolism62.334630350.01847329TYMP, NT5C3A, RRM2, UPP1, PNP, CMPK2
Upregulatedhsa04620Toll-like receptor signaling pathway62.334630350.01989591IRF7, CXCL9, CXCL8, IL1B, STAT1, CXCL10
Upregulatedhsa05146Amoebiasis62.334630350.01989591ARG1, CXCL8, IL1B, SERPINB4, SERPINB13, SERPINB3
Upregulatedhsa01100Metabolic pathways2710.505836580.03117996XDH, GDA, KYNU, HSD17B2, NT5C3A, GALNT6, CYP2C18, UPP1, AASS, PNP, CMPK2, ARG1, TYMP, HPSE, ALOX12B, FUT2, SPTLC2, DHRS9, HYAL4, ST6GALNAC1, SQLE, RRM2, AKR1B10, LIPG, GK, SMPD3, PLA2G4D
Upregulatedhsa04110Cell cycle62.334630350.0359891CCNB1, CCNE1, CDK1, CDC45, TTK, CDC20
Upregulatedhsa04060Cytokine-cytokine receptor interaction83.1128404670.05301106CCL20, CXCL13, CXCL9, CXCL8, IL1B, CXCR2, IL7R, CXCL10
Upregulatedhsa04623Cytosolic DNA-sensing pathway41.5564202330.06819191IRF7, IL1B, AIM2, CXCL10
Upregulatedhsa04668TNF signaling pathway51.9455252920.07110534CXCL1, NOD2, CCL20, IL1B, CXCL10
Upregulatedhsa04115p53 signaling pathway41.5564202330.07600871CCNB1, CCNE1, CDK1, RRM2
Upregulatedhsa04622RIG-I-like receptor signaling pathway41.5564202330.08420339ISG15, IRF7, CXCL8, CXCL10
Downregulatedhsa04960 Aldosterone-regulated sodium reabsorption33.4883720930.01441893HSD11B1, NR3C2, ATP1A2
Downregulatedhsa03320PPAR signaling pathway33.4883720930.03821865ACOX2, LPL, ACADL

[i] KEGG, Kyoto Encyclopedia of Genes and Genomes; DEGs, differentially expressed genes.

PPI network construction and hub gene selection

The online database STRING was used to obtain PPI information on the 373 DEGs, including the 277 upregulated and 96 downregulated genes and the PPI network, with 2 notable functional modules, was constructed with use of Cytoscape software (Fig. 5A). Hub genes were then calculated using the cytoHubba app from the network we constructed. As a result of these calculations, 17 genes with the highest scores were considered as hub genes and were automatically divided into 2 groups exactly corresponding to the modules in Fig. 5A. One group consisted of TTK, AURKA, DLGAP5, HMMR, CDC45, CENPE, SPC25, MCM10, NDC80, RRM2, CKS2 and NUF2, which are genes involved in the cell cycle, mitosis and proliferation. The second group consisted of IFI6, ISG20, IFIT1, RSAD2 and IFI27, all of which belong to IFN-α-inducible genes (Fig. 5B). Notably, these 17 hub genes all belong to the upregulated genes of the DEGs we obtained, which further demonstrated the importance of these upregulated genes in the molecular pathogenesis of psoriasis.

Hub gene expression levels in scalp psoriasis

To investigate whether scalp psoriasis displayed a similar gene expression profile as that of skin psoriasis, 13 pairs of scalp lesional and adjacent non-lesional samples were selected from GSE75343 (Table I). With use of the online analysis tool, GEO2R, expression levels of these 17 hub genes were determined. The results revealed that statistically significant differences were obtained in the expression of IFI6, IFI27, RSAD2, ISG20, MCM10 and SPC25 (Fig. 6), but not in the other hub genes (data not shown). Further analysis revealed that 4 out of 6 IFN-α-inducible genes exhibited significant differences with regard to gene expression, while in genes involved in the cell cycle, mitosis and proliferation, only 2 of them exhibited differences in gene expression.

Discussion

Psoriasis, one of the most common skin ailments, afflicts millions of people worldwide. In addition to its negative aspects on physical and mental health, the cost of psoriasis places a huge burden on both individuals and society (17). Although dozens of medications are available for relief of the symptoms of this disease, no cure for psoriasis currently exists. Therefore, it is clear that the identification of pivotal molecules that play critical roles in the pathogenesis of this disease for potential development of therapeutic targets represents an important area of investigation.

Gene expression microarrays provide a comprehensive view of genome-wide expression profiles of clinical samples and have been widely used to analyze genes which are differentially expressed in psoriasis. However, few studies exist which have integrated such high-throughput gene expression microarray data of paired lesional and non-lesional skin samples. In the present study, gene expression profiles of 175 pairs of psoriatic skin samples and the corresponding normal tissues from 5 GEO data sets were integrated and analyzed with use of bioinformatic methods. Our results demonstrated several important pathways and the pivotal genes associated with the molecular pathogenesis of psoriasis.

Psoriasis is an immune-mediated inflammatory cutaneous disease characterized by an overt proliferation and differentiation of keratinocytes (1). Our GO biological process enrichment results, especially with regard to upregulated genes, included immune responses, keratinization, inflammatory responses and keratinocyte differentiation, all of which are commonly accepted components of the pathogenesis and pathological changes of psoriasis. In addition, the enrichment in defense responses and responses to wound healing processes indicates two important psoriatic precipitating factors: infection (18) and trauma (Koebner phenomena) (19), respectively, both of which are associated with the activation of innate immunity involved in the initial pathogenesis of psoriasis (20). Additional reported risk factors include smoking (21), alcohol (22) and obesity (23). In the cellular component enrichment analysis, in addition to mitosis-associated components such as chromosome kinetochore and the Ndc80 complex, enrichment in the extracellular matrix of both up- or downregulated genes revealed the significance of this component. The extracellular matrix (ECM) is a collection of non-cellular molecular networks that regulate diverse cellular functions, such as growth, migration and homeostasis (24,25). The ECM is composed of interstitial matrix and basement membrane, both of which are reported to be involved in the development of psoriasis. Findings from a guttate psoriasis prognosis study, indicate that psoriasis disease progression is believed to be governed by the triggering of humoral immune responses, which could produce extracellular antibodies to neutralize the streptococcal lytic enzyme and prevent disruption of the laminin layer in the basement membrane caused by the enzyme (26). Recently, neutrophil extracellular traps (NETs), which are web-like structures consisting of DNA associated with histones, antimicrobial peptides and enzymes (27,28), were reported to act as a source of autoantigens which contribute to the occurrence of several autoimmune diseases (29,30), including psoriasis. For example, Lin et al reported that mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis (31). In molecular function enrichment analysis, it was observed that in upregulated genes, several GO terms indicated endopeptidase inhibitor activity, which contains a family of serine protease inhibitors (serpins). Serpins, such as SERPINA3, SERPINB4, SERPINA1, SERPINB12, SERPINB3 and SERPINB13 in our enrichment gene list represent a broad family of protease inhibitors that utilize conformational changes to inhibit target enzymes (32); and it has been suggested that these serpins play a role in psoriatic pathogenesis. Similar to the results obtained in our analysis, Johnston et al detected upregulation of two endogenous protease inhibitors, serpins A1 and A3, both of which are present in psoriasis vulgaris and generalized pustular psoriasis. These serpins may play a counter-regulated role to control the activity of IL-36, whose activation requires N-terminal peptide cleavage by neutrophil serine protease (33). Such a negative regulatory effect, although unlikely to balance the protease expression revealed in the study by Lin et al (31), may provide for new insights into the development of psoriasis therapy.

The results from our KEGG pathway analysis revealed that a high enrichment in metabolic and viral infection pathways was present in upregulated genes. There were 26 genes enriched in metabolic pathways, including XDH, GDA, KYNU, HSD17B2, NT5C3A, GALNT6, CYP2C18, UPP1, AASS, PNP, CMPK2, ARG1, TYMP, HPSE, ALOX12B, FUT2, SPTLC2, DHRS9, HYAL4, ST6GALNAC1, SQLE, RRM2, AKR1B10, LIPG, GK, SMPD3 and PLA2G4D. Among these genes, ALOX12B, one of the lipoxygenases, is reported to play an important role in the regulation of epithelial proliferation, differentiation, wound healing and inflammatory skin diseases (34). PLA2G4D, a member of phospholipase A2, was revealed to have a strong gene expression in the upper spinous layer of psoriatic epidermis, while in normal skin the expression of PLA2G4D was not detected (35). The expression or functions of the other genes in our list have received little attention with regard to their roles in cutaneous disorders. Therefore, these genes may provide important new research targets for the understanding and treatment of psoriasis. Most of the genes enriched in viral infection KEGG pathways are IFN-α-inducible genes which belong to one group of the hub genes in the PPI network.

The PPI network was constructed by Cytoscape software and hub genes were then determined. With this analysis, 17 genes were identified and divided into 2 groups according to protein-protein interactions. One group of these were IFN-α-inducible genes, which were also enriched in KEGG viral infection pathways, and included IFI6, IFI27, IFIT1, RSAD2 and ISG20. A role for IFN-α in psoriasis development has been gradually revealed. For example, Garcia-Romo et al demonstrated that in the initial phase of disease development, cutaneous accumulated plasmacytoid pre-dendritic cells become activated and produce IFN-α, which then drives the stimulation of autoimmune T cells in pre-psoriatic skin (30). Such a mechanism provides an explanation for the role of innate immunity in connecting environmental triggers, such as viral or bacterial infection and wound healing with disease-associated autoimmune T cells. This also clarifies the reason for an absence of IFN-α in our analysis, since the samples we selected were all from chronic plaque psoriasis patients. The expression of IFN-α-inducible genes in our study was also observed in scalp psoriatic samples, demonstrating an important role for IFN-α in the pathogenesis of psoriasis within different skin areas. The other group of genes including, CSK2, CDC45, MCM10, SPC25, NDC80, NUF2, AURKA, CENPE, RRM2, DLGP5, HMMR and TTK, were associated with the regulation of the cell cycle, mitosis and proliferation (36,37). Notably, there are two kinases in this group of hub genes: Aurora kinase A, essential for chromosome segregation (38) and TTK, whose expression is at high levels in tissues which contain large numbers of proliferating cells (39). While the relationship between these kinases and psoriasis development is yet unclear, there exists a potentially important role that they may play in the pathogenesis of psoriasis. In contrast to the results in the IFN-α-inducible gene group, the expression of most hub genes associated with the cell cycle and proliferation in scalp psoriatic samples (except for MCM10 and SPC25), revealed no significant differences from that of paired control samples. Within the scalp area a large proportion of follicles are in anagen, which may contribute to a set of highly expressed genes associated with the cell cycle and proliferation. This can be contrasted with that of skin samples from other areas where most hair follicles are in catagen or telophase. Histologically, in the initial stages of this disease scalp psoriasis mainly affects the interfollicular epidermis with perifollicular inflammation (13), while later stages include destruction of hair follicles with perifollicular fibrosis and hair loss (40). Based on these findings, it was hypothesized that the expression of these cell cycle-related genes, which are assumed to be at high expression levels in psoriatic samples, is relatively reduced in scalp psoriatic samples where hair follicle destruction occurs as compared to normal scalp tissues, as reflected in our results.

Although a similar bioinformatical study on psoriasis has been performed (7), in our present study, we limited our data sets to paired lesional and non-lesional psoriatic skin samples and performed DEG analysis with use of paired-sample t-tests in each data set. An overlap method was subsequently employed to combine these DEG results as a means to obtain an overall set of DEGs corresponding with that of each data set. With use of these strict screening methods, we consider that our results have a relatively high degree of specificity for detecting pivotal disease-associated molecules, however the resultant low sensitivity would be considered as a limitation of this study. In our future research, if ethical approval is obtained, RT-qPCR validation of these identified target genes in clinical samples will be conducted. In conclusion, through a comprehensive bioinformatic re-analysis of these original GEO data, an overall view regarding the molecular pathogenesis of psoriasis and the potential for identification of therapeutic targets for this disease was provided.

Acknowledgements

Not applicable.

Funding

The present study was supported by the National Natural Science Foundation of China (grant no. 81673070) and the National Key Basic Research Program of China (grant no. 2013CB531604).

Availability of data and materials

All data generated or analyzed in the present study are included in this published article.

Authors' contributions

YJZ collected the online microarray data and the corresponding clinical information and drafted the manuscript. YJZ and YZS performed the bioinformatic and statistical analysis. XHG and RQQ contributed to the study design and performed the proofreading and revision of the manuscript. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

All authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

GEO

Gene Expression Omnibus

DEG

differentially expressed gene

GO

gene ontology

KEGG

Kyoto Encyclopedia of Genes and Genomes

PPI

protein-protein interaction

References

1 

Greb JE, Goldminz AM, Elder JT, Lebwohl MG, Gladman DD, Wu JJ, Mehta NN, Finlay AY and Gottlieb AB: Psoriasis. Nat Rev Dis Primers. 2:160822016. View Article : Google Scholar : PubMed/NCBI

2 

Parisi R, Symmons DP, Griffiths CE and Ashcroft DM; Identification Management of Psoriasis, Associated ComorbidiTy (IMPACT) project team, : Global epidemiology of psoriasis: A systematic review of incidence and prevalence. J Invest Dermatol. 133:377–385. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Martinez-Garcia E, Arias-Santiago S, Valenzuela-Salas I, Garrido-Colmenero C, Garcia-Mellado V and Buendia-Eisman A: Quality of life in persons living with psoriasis patients. J Am Acad Dermatol. 71:302–307. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Egeberg A, Thyssen JP, Wu JJ and Skov L: Risk of first-time and recurrent depression in patients with psoriasis: A population-based cohort study. Br J Dermatol. 180:116–121. 2019. View Article : Google Scholar : PubMed/NCBI

5 

Ainali C, Valeyev N, Perera G, Williams A, Gudjonsson JE, Ouzounis CA, Nestle FO and Tsoka S: Transcriptome classification reveals molecular subtypes in psoriasis. BMC genomics. 13:4722012. View Article : Google Scholar : PubMed/NCBI

6 

Mei R and Mei X: Screening of skin lesion-associated genes in patients with psoriasis by meta-integration analysis. Dermatology. 233:277–288. 2017. View Article : Google Scholar : PubMed/NCBI

7 

Sevimoglu T and Arga KY: Computational systems biology of psoriasis: Are we ready for the age of omics and systems biomarkers? OMICS. 19:669–687. 2015. View Article : Google Scholar : PubMed/NCBI

8 

Yao Y, Richman L, Morehouse C, de los Reyes M, Higgs BW, Boutrin A, White B, Coyle A, Krueger J, Kiener PA and Jallal B: Type I interferon: Potential therapeutic target for psoriasis? PLoS One. 3:e27372008. View Article : Google Scholar : PubMed/NCBI

9 

Suárez-Fariñas M, Li K, Fuentes-Duculan J, Hayden K, Brodmerkel C and Krueger JG: Expanding the psoriasis disease profile: Interrogation of the skin and serum of patients with moderate-to-severe psoriasis. J Invest Dermatol. 132:2552–2564. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Correa da Rosa J, Kim J, Tian S, Tomalin LE, Krueger JG and Suárez-Fariñas M: Shrinking the psoriasis assessment gap: Early gene-expression profiling accurately predicts response to long-term treatment. J Invest Dermato. 137:305–312. 2017. View Article : Google Scholar

11 

Bigler J, Rand HA, Kerkof K, Timour M and Russell CB: Cross-study homogeneity of psoriasis gene expression in skin across a large expression range. PLoS One. 8:e522422013. View Article : Google Scholar : PubMed/NCBI

12 

Russell CB, Rand H, Bigler J, Kerkof K, Timour M, Bautista E, Krueger JG, Salinger DH, Welcher AA and Martin DA: Gene expression profiles normalized in psoriatic skin by treatment with brodalumab, a human anti-IL-17 receptor monoclonal antibody. J Immunol. 192:3828–3836. 2014. View Article : Google Scholar : PubMed/NCBI

13 

Ruano J, Suárez-Fariñas M, Shemer A, Oliva M, Guttman-Yassky E and Krueger JG: Molecular and cellular profiling of scalp psoriasis reveals differences and similarities compared to skin psoriasis. PLoS One. 11:e01484502016. View Article : Google Scholar : PubMed/NCBI

14 

Sherman BT, Huang da W, Tan Q, Guo Y, Bour S, Liu D, Stephens R, Baseler MW, Lane HC and Lempicki RA: DAVID Knowledgebase: A gene-centered database integrating heterogeneous gene annotation resources to facilitate high-throughput gene functional analysis. BMC Bioinformatics. 8:4262007. View Article : Google Scholar : PubMed/NCBI

15 

Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, et al: The STRING database in 2017: Quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 45:D362–D368. 2017. View Article : Google Scholar : PubMed/NCBI

16 

Chin CH, Chen SH, Wu HH, Ho CW, Ko MT and Lin CY: cytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 8 (Suppl 4):S112014. View Article : Google Scholar : PubMed/NCBI

17 

Ishida-Yamamoto A and Iizuka H: Structural organization of cornified cell envelopes and alterations in inherited skin disorders. Exp Dermatol. 7:1–10. 1998. View Article : Google Scholar : PubMed/NCBI

18 

Telfer NR, Chalmers RJ, Whale K and Colman G: The role of streptococcal infection in the initiation of guttate psoriasis. Arch Dermatol. 128:39–42. 1992. View Article : Google Scholar : PubMed/NCBI

19 

Morhenn VB: The relationship of wound healing with psoriasis and multiple sclerosis. Adv Wound Care (New Rochelle). 7:185–188. 2018. View Article : Google Scholar : PubMed/NCBI

20 

Sweeney CM, Tobin AM and Kirby B: Innate immunity in the pathogenesis of psoriasis. Arch Dermatol Res. 303:691–705. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Armstrong AW, Harskamp CT, Dhillon JS and Armstrong EJ: Psoriasis and smoking: A systematic review and meta-analysis. Br J Dermatol. 170:304–314. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Qureshi AA, Dominguez PL, Choi HK, Han J and Curhan G: Alcohol intake and risk of incident psoriasis in US women: A prospective study. Arch Dermatol. 146:1364–1369. 2010. View Article : Google Scholar : PubMed/NCBI

23 

Jensen P and Skov L: Psoriasis and obesity. Dermatology. 232:633–639. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Frantz C, Stewart KM and Weaver VM: The extracellular matrix at a glance. J Cell Sci. 123:4195–4200. 2010. View Article : Google Scholar : PubMed/NCBI

25 

Theocharis AD, Skandalis SS, Gialeli C and Karamanos NK: Extracellular matrix structure. Adv Drug Deliv Rev. 97:4–27. 2016. View Article : Google Scholar : PubMed/NCBI

26 

McFadden J, Fry L, Powles AV and Kimber I: Concepts in psoriasis: Psoriasis and the extracellular matrix. Br J Dermatol. 167:980–986. 2012. View Article : Google Scholar : PubMed/NCBI

27 

Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y and Zychlinsky A: Neutrophil extracellular traps kill bacteria. Science. 303:1532–1535. 2004. View Article : Google Scholar : PubMed/NCBI

28 

Brinkmann V and Zychlinsky A: Neutrophil extracellular traps: Is immunity the second function of chromatin? J Cell Biol. 198:773–783. 2012. View Article : Google Scholar : PubMed/NCBI

29 

Kessenbrock K, Krumbholz M, Schönermarck U, Back W, Gross WL, Werb Z, Gröne HJ, Brinkmann V and Jenne DE: Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 15:623–625. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, et al: Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci Transl Med. 3:73ra202011. View Article : Google Scholar : PubMed/NCBI

31 

Lin AM, Rubin CJ, Khandpur R, Wang JY, Riblett M, Yalavarthi S, Villanueva EC, Shah P, Kaplan MJ and Bruce AT: Mast cells and neutrophils release IL-17 through extracellular trap formation in psoriasis. J Immunol. 187:490–500. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI and Whisstock JC: An overview of the serpin superfamily. Genome Biol. 7:2162006. View Article : Google Scholar : PubMed/NCBI

33 

Johnston A, Xing X, Wolterink L, Barnes DH, Yin Z, Reingold L, Kahlenberg JM, Harms PW and Gudjonsson JE: IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis. J Allergy Clin Immunol. 140:109–120. 2017. View Article : Google Scholar : PubMed/NCBI

34 

Krieg P and Fürstenberger G: The role of lipoxygenases in epidermis. Biochim Biophys Acta. 1841:390–400. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Chiba H, Michibata H, Wakimoto K, Seishima M, Kawasaki S, Okubo K, Mitsui H, Torii H and Imai Y: Cloning of a gene for a novel epithelium-specific cytosolic phospholipase A2, cPLA2delta, induced in psoriatic skin. J Biol Chem. 279:12890–12897. 2004. View Article : Google Scholar : PubMed/NCBI

36 

Kudalkar EM, Scarborough EA, Umbreit NT, Zelter A, Gestaut DR, Riffle M, Johnson RS, MacCoss MJ, Asbury CL and Davis TN: Regulation of outer kinetochore Ndc80 complex-based microtubule attachments by the central kinetochore Mis12/MIND complex. Proc Natl Acad Sci USA. 112:E5583–E5589. 2015. View Article : Google Scholar : PubMed/NCBI

37 

Santaguida S and Musacchio A: The life and miracles of kinetochores. EMBO J. 28:2511–2531. 2009. View Article : Google Scholar : PubMed/NCBI

38 

DeLuca KF, Meppelink A, Broad AJ, Mick JE, Peersen OB, Pektas S, Lens SMA and DeLuca JG: Aurora A kinase phosphorylates Hec1 to regulate metaphase kinetochore-microtubule dynamics. J Cell Bio. 217:163–177. 2018. View Article : Google Scholar

39 

Mills GB, Schmandt R, McGill M, Amendola A, Hill M, Jacobs K, May C, Rodricks AM, Campbell S and Hogg D: Expression of TTK, a novel human protein kinase, is associated with cell proliferation. J Biol Chem. 267:16000–16006. 1992.PubMed/NCBI

40 

George SM, Taylor MR and Farrant PB: Psoriatic alopecia. Clin Exp Dermatol. 40:717–721. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

July 2019
Volume 20 Issue 1

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Zhang, Y., Sun, Y., Gao, X., & Qi, R. (2019). Integrated bioinformatic analysis of differentially expressed genes and signaling pathways in plaque psoriasis. Molecular Medicine Reports, 20, 225-235. https://doi.org/10.3892/mmr.2019.10241
MLA
Zhang, Y., Sun, Y., Gao, X., Qi, R."Integrated bioinformatic analysis of differentially expressed genes and signaling pathways in plaque psoriasis". Molecular Medicine Reports 20.1 (2019): 225-235.
Chicago
Zhang, Y., Sun, Y., Gao, X., Qi, R."Integrated bioinformatic analysis of differentially expressed genes and signaling pathways in plaque psoriasis". Molecular Medicine Reports 20, no. 1 (2019): 225-235. https://doi.org/10.3892/mmr.2019.10241