Key genes associated with pancreatic cancer and their association with outcomes: A bioinformatics analysis

  • Authors:
    • Jiajia Wu
    • Zedong Li
    • Kai Zeng
    • Kangjian Wu
    • Dong Xu
    • Jun Zhou
    • Lijian Xu
  • View Affiliations

  • Published online on: June 3, 2019     https://doi.org/10.3892/mmr.2019.10321
  • Pages: 1343-1352
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Abstract

Pancreatic cancer is a highly malignant neoplastic disease of the digestive system. In the present study, the dataset GSE62165 was downloaded from the Gene Expression Omnibus (GEO) database. GSE62165 contained the data of 118 pancreatic ductal adenocarcinoma samples (38 early‑stage tumors, 62 lymph node metastases and 18 advanced tumors) and 13 control samples. Differences in the expression levels of genes between normal tissues and early‑stage tumors were investigated. A total of 240 differentially expressed genes (DEGs) were identified using R software 3.5 (137 upregulated genes and 103 downregulated genes). Then, the differentially expressed genes were subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis. The following 18 core genes were identified using Cytoscape, based on the protein‑interaction network of DEGs determined using the online tool STRING: EGF, ALB, COL17A1, FN1, TIMP1, PLAU, PLA2G1B, IGFBP3, PLAUR, VCAN, COL1A1, PNLIP, CTRL, PRSS3, COMP, CPB1, ITGA2 and CEL. The pathways of the core genes were primarily associated with pancreatic secretion, protein digestion and absorption, and focal adhesion. Finally, survival analyses of core genes in pancreatic cancer were conducted using the UALCAN online database. It was revealed that PLAU and COL17A1 were significantly associated with poor prognosis (P<0.05). The expression levels of genes in primary pancreatic cancer tissues were then compared; only one gene, COL17A1, was identified to be significantly differentially expressed. Finally, another dataset from GEO, GSE28735, was analyzed to verify the upregulated expression of COL17A1. Taken together, the results of the present study have indicated that the expression of COL17A1 gene may be associated with the occurrence and development of pancreatic cancer.

Introduction

Pancreatic cancer is a highly malignant neoplasm of the digestive system that accounts for >200,000 deaths/year globally (1). The incidence of pancreatic cancer is low compared with that of lung, breast, colorectal and gastric cancers; however, it is associated with a very high mortality rate. It has been reported that the incidence of pancreatic cancer is very similar to the associated mortality rate; the reported 5-year survival rate of patients with pancreatic cancer is <6% (2). The mortality rate of patients with pancreatic cancer ranks fourth among common cancers, and is predicted to rise to second within a decade (3). A number of factors have been identified as contributing to the etiopathogenesis of pancreatic cancer, including heredity, smoking, high-fat diet, chronic pancreatitis and consumption of nitrous acid compounds (4). Due to the latency of pancreatic cancer, the majority of patients are diagnosed at an advanced stage, when tumor tissue has already infiltrated the surrounding tissues and has formed distant metastases, decreasing the usefulness of surgical interventions (5). As a result of drug resistance, the efficacy of postoperative adjuvant therapy has also been very unsatisfactory (6). Carbohydrate antigen 19-9 (CA19-9) is the most frequently used marker for the clinical diagnosis of cancer; the reported sensitivity and specificity of CA19-9 for the diagnosis of pancreatic cancer is 69-93 and 46–98%, respectively (7). Therefore, early diagnosis and treatment are important to improve the prognosis and survival of patients with pancreatic cancer.

At present, high-throughput sequencing is employed in a variety of contexts, such as the discovery of gene mutations and chromosomal translocations that are closely associated with the occurrence and development of tumors (810). High-throughput sequencing may be useful for the diagnosis of cancer and development of targeted therapies. These analyses may provide novel insights to guide subsequent research.

Materials and methods

Microarray data

The gene expression profile of GSE62165 (11) was downloaded from the GEO database (12). The data were created using the GPL13667 Affymetrix® Human Genome U219 array (Affymetrix; Thermo Fisher Scientific, Inc.). GSE62165 contained data on 118 pancreatic ductal adenocarcinoma (PDAC) samples and 13 control samples. Data were standardized using the robust multi-array average (RMA) algorithm using limma package (version 3.38.3) (13). In addition, a separate dataset, GSE28735 (14,15), was used to verify the results. The expression profiles included 45 matched pairs of pancreatic tumor and adjacent non-tumor tissues from 45 patients with PDAC. The Cancer Genome Atlas (TCGA; http://cancergenome.nih.gov/) contains genomic sequencing data involving 33 species of cancer.

Identification of differentially expressed genes (DEGs)

The limma package (version 3.38.3) (13) was used to identify DEGs between pancreatic cancer tissue and normal pancreatic tissue samples in R software (version 3.5; http://www.R-project.org). |log2 Fold Change (FC)|>3.0 and adjusted P-value <0.05 were considered to be the threshold for differential gene identification.

Gene Ontology (GO) and Kyoto Encyclopedia of genes and genomes (KEGG) pathway analysis of DEGs

GO (http://www.geneontology.org/) and the KEGG (https://www.kegg.jp/) (1619) were used to analyze the function of DEGs using the cluster Profiler R package (20). P<0.05 was considered to indicate a statistically significant difference in functional enrichment analysis.

Core genes screening from the protein-protein interaction (PPI) network

A PPI network for the DEGs was generated using the STRING database (https://string-db.org/). Then, Cytoscape (version 3.6.1) (21) was employed, and a plug-in termed cytohubba (22) was integrated into the software. The plug-in provides 12 types of topological analysis methods [Maximal Clique Centrality, Maximum Neighborhood Component (MNC), Density of MNC, Degree, Edge Percolated Component, Bottleneck, EcCentricity, Closeness, Radiality, Betweenness, Stress and Clustering Coefficient). Using 12 analysis methods, we identified the top 18 genes as core genes.

Expression levels and survival analysis of core genes in pancreatic cancer

UALCAN (http://ualcan.path.uab.edu/index.html) (23) was employed to perform survival analysis based on the information of TCGA database. Survival analysis was performed via the Kaplan-Meier method using 18 identified core genes, based on their core gene expression levels in pancreatic adenocarcinoma (PAAD). P<0.05 was considered to be statistically significant. The P-value was calculated using log-rank test. The ‘scaled_estimate’ column provided the potential transcripts produced by each gene. The ‘scaled_estimate’ was multiplied by 106 to obtain a transcripts per million (TPM) expression value (24). Gene expression levels in tumor tissues exhibited notable inter-individual variability. High expression indicated that the TPM value was above the upper quartile value. Low expression indicated that the TPM value was equal or below the upper quartile value.

Verification of results

The findings from the bioinformatics analyses were validated using the dataset GSE28735 from the GEO database. The expression profiles included 45 matched pairs of pancreatic tumor and adjacent non-tumor tissues from 45 patients with PDAC. The online analysis tool GEO2R (https://www.ncbi.nlm.nih.gov/geo/geo2r/) was used to determine the expression of DEGs. We further verified the expression of COL17A1.

Results

Analysis of DEGs

The selected chipset GSE62165 included 118 PDAC samples and 13 control samples. Differences in gene expression profiles were analyzed using 38 early-stage tumors and 13 normal tissues. A total of 240 DEGs (adjusted P-value <0.05; |log2FC|≥3.0) were identified using R version 3.5 software, including 137 upregulated genes and 103 downregulated genes (Table I). The heat map of genes with upregulated expression is presented in Fig. 1. A volcanic map of all genes is presented in Fig. 2.

Table I.

Top 20 differentially expressed genes in early-stage pancreatic cancer tissues based on Log2FC.

Table I.

Top 20 differentially expressed genes in early-stage pancreatic cancer tissues based on Log2FC.

A, Upregulated genes

Gene symbolLog2FCAdjusted P-value
COL1A15.9240335 3.17×10−16
KRT175.5334643 4.10×10−12
CEACAM55.3990511 1.66×10−09
S100P5.2665291 1.66×10−13
COL10A15.2258147 1.17×10−17
SERPINB55.1642588 5.50×10−15
GJB25.0747799 7.98×10−18
COL17A15.0501325 1.80×10−11
CXCL55.0384043 1.28×10−11
TMPRSS45.0203823 2.37×10−16
SDR16C54.9961337 3.16×10−16
CTHRC14.9626426 7.77×10−20
COL11A14.9350078 6.41×10−17
SLC6A144.8841916 2.47×10−15
MMP114.8824426 3.14×10−16
SULF14.721966 2.96×10−17
FN14.6424864 2.99×10−16
POSTN4.6415794 1.33×10−16
CCL184.5489901 1.41×10−11
MUC44.5022059 1.25×10−09

B, Downregulated genes

Gene symbolLog2FCAdjusted P-value

SYCN−6.6535946 2.74×10−07
SERPINI2−6.2894352 8.73×10−09
AQP8−6.2356139 2.11×10−10
AMY1A−6.1790263 4.38×10−10
ALB−6.1165814 2.16×10−08
CELA2A−6.0845313 2.83×10−06
PNLIPRP1−6.0676353 6.52×10−10
CTRL−5.9224624 1.73×10−06
PDIA2−5.9185276 4.65×10−09
CPA1−5.804844 5.21×10−06
TMED6−5.7967792 2.37×10−10
CELP−5.7183603 1.15×10−10
AQP12A−5.6598636 3.88×10−14
CUZD1−5.5766969 1.68×10−06
CELA2B−5.5649112 2.23×10−05
CPA2−5.55513 3.43×10−06
CELA3A−5.5508171 1.84×10−05
GP2−5.5087922 1.20×10−06
ERP27−5.4765153 7.39×10−09
CPA1−5.4417426 1.81×10−05

[i] Log2FC, log2 fold change.

Enrichment analysis of DEGs

To investigated the distribution of DEGs, GO and KEGG analysis of upregulated and downregulated genes was conducted. GO analysis revealed that the ‘biological processes’ (BPs) of upregulated genes mainly included extracellular matrix organization, extracellular structure organization and collagen catabolic process. ‘Molecular functions’ (MFs) of upregulated DEGs primarily included extracellular matrix structural constituents, glycosaminoglycan binding and cytokine activity. For the ‘cell components’ (CCs) identified by GO analysis, proteinaceous extracellular matrix, extracellular matrix component and endoplasmic reticulum lumen were the most prominent (Table II). For downregulated DEGs, the main enriched BPs were digestion, lipid digestion and sulfur amino acid metabolic process, whereas the primary MFs were exopeptidase activity, serine-type endopeptidase activity and serine-type peptidase activity (Table II). Figs. 3 and 4 present the associations between genes and enrichment results, indicating the genes that were highly changed between the two conditions.

Table II.

GO analysis of differentially expressed genes in pancreatic cancer.

Table II.

GO analysis of differentially expressed genes in pancreatic cancer.

A, Upregulated genes

CategoryIDDescriptionCountP-value
GOBPGO:0030198Extracellular matrix organization22 9.83×10−21
GOBPGO:0043062Extracellular structure organization22 1.05×10−20
GOBPGO:0030574Collagen catabolic process10 2.16×10−13
GOBPGO:0044243Multicellular organismal catabolic process10 6.89×10−13
GOBPGO:0032963Collagen metabolic process11 4.16×10−12
GOMFGO:0005201Extracellular matrix structural constituent8 1.09×10−09
GOMFGO:0005539Glycosaminoglycan binding7 2.85×10−05
GOMFGO:0005125Cytokine activity7 3.50×10−05
GOMFGO:0008009Chemokine activity4 4.62×10−05
GOMFGO:1901681Sulfur compound binding7 4.91×10−05
GOCCGO:0005578Proteinaceous extracellular matrix20 1.05×10−17
GOCCGO:0044420Extracellular matrix component10 4.54×10−11
GOCCGO:0005788Endoplasmic reticulum lumen13 1.70×10−10
GOCCGO:0005581Collagen trimer8 2.20×10−09
GOCCGO:0098644Complex of collagen trimers5 1.32×10−08

B, Downregulated genes

CategoryID DescriptionCountP-value

GOBPGO:0007586Digestion10 7.20×10−10
GOBPGO:0044241Lipid digestion5 1.00×10−08
GOBPGO:0000096Sulfur amino acid metabolic process4 1.27×10−05
GOBPGO:0009235Cobalamin metabolic process3 6.62×10−05
GOBPGO:1901605α-Amino acid metabolic process6 1.76×10−4
GOMFGO:0008238Exopeptidase activity8 7.37×10−09
GOMFGO:0004252Serine-type endopeptidase activity10 2.66×10−08
GOMFGO:0008236Serine-type peptidase activity10 7.39×10−08
GOMFGO:0008235Metalloexopeptidase activity6 8.31×10−08
GOMFGO:0017171Serine hydrolase activity10 8.76×10−08

[i] GO, Gene Ontology; MF, molecular function; CC, cell component; BP, biological process.

Table III presents KEGG pathway analysis of the DEGs, revealing that the upregulated genes were mainly located in extracellular matrix (ECM)-receptor interaction, protein digestion and absorption, and focal adhesion pathways. Conversely, downregulated genes were primarily located in pancreatic secretion, protein digestion and absorption, and fat digestion and absorption pathways. Figs. 5 and 6 present the distribution of the major KEGG pathways generated using clusterProfiler. It was observed that ECM-receptor interactions (Fig. 5) and pancreatic secretion (Fig. 6) were the pathways most enriched with up- and downregulated DEGs, respectively.

Table III.

KEGG pathway analysis of differentially expressed genes in pancreatic cancer.

Table III.

KEGG pathway analysis of differentially expressed genes in pancreatic cancer.

A, Upregulated genes

IDDescriptionCountP-value
hsa04512Extracellular matrix-receptor interaction7 2.23×10−07
hsa04974Protein digestion and absorption7 4.25×10−07
hsa04510Focal adhesion7 8.15×10−05
hsa04657Interleukin-17 signaling pathway5 1.32×10−4
hsa05146Amebiasis5 1.53×10−4

B, Downregulated genes

ID DescriptionCountP-value

hsa04972Pancreatic secretion13 3.63×10−16
hsa04974Protein digestion and absorption8 1.03×10−08
hsa04975Fat digestion and absorption6 4.10×10−08
hsa00561Glycerolipid metabolism4 2.27×10−4
hsa00260Glycine, serine and threonine metabolism3 1.01×10−3

[i] KEGG, Kyoto Encyclopedia of Genes and Genomes.

Screening of core genes in the PPI

Based on the information in the STRING database and using 12 types of calculation methods in Cytoscape, the following 18 core genes were identified: EGF, ALB, COL17A1, FN1, TIMP1, PLAU, PLA2G1B, IGFBP3, PLAUR, VCAN, COL1A1, PNLIP, CTRL, PRSS3, COMP, CPB1, ITGA2 and CEL. These core genes were associated with each other and may exhibit synergistic effects in the development of pancreatic cancer (Fig. 7). According to the previous enrichment analysis, the core genes, were mainly located in pancreatic secretion, protein digestion and absorption, and focal adhesion pathways.

Gene expression level and survival analysis

Notably, COL17A1 and PLAU genes were the only genes associated with survival. Following the identification of core genes, survival analysis for PAAD was performed using UALCAN. PLAU [which encodes the serine protease urokinase-type plasminogen activator (uPA); Fig. 8] and COL17A1 [which encodes collagen type XVII α1 chain (COL17A1); Fig. 9] were demonstrated to be significantly associated with survival (P<0.05). Subsequently, the expression levels of genes in primary pancreatic cancer were compared; only one gene was identified to be significantly differentially expressed, COL17A1, whereas PLAU was not significantly differentially expressed. The expression levels of COL17A1 were analyzed in TCGA database, and the results were consistent with those of the aforementioned differential gene analysis; COL17A1 was significantly upregulated in PAAD tumor tissues compared with normal tissues (P=1.62×10−12; Fig. 10).

Verification of COL17A1

Differences in gene expression between 45 pancreatic cancer patients and 45 normal pancreatic tissues were analyzed. In particular, the expression level of COL17A1 was investigated. The results of the analysis to verify the importance of COL17A1 are presented in Table IV; it was observed that COL17A1 was significantly upregulated in pancreatic tumor tissue in the two GEO databases.

Table IV.

Differential expression of COL17A1 in pancreatic cancer tissues in two databases.

Table IV.

Differential expression of COL17A1 in pancreatic cancer tissues in two databases.

DatabaseGeneLog2FCAdjusted P-value
GSE62165COL17A15.0501325 1.8×10−11
GSE28735COL17A11.893626 6.56×10−13

[i] Log2FC, Log2 fold change; COL17A1, collagen type XVII α1 chain.

Discussion

The incidence of pancreatic cancer and the associated mortality rates have exhibited an increasing trend in previous years (3). Studies have reported that patients with pancreatic cancer survive for only 4 months on average without treatment; even in patients who undergo treatment, the survival is not significantly extended (25). Therefore, accurate early diagnosis of pancreatic cancer and the development of effective targeted therapy is of major importance.

A previous study identified core genes in pancreatic cancer that were reported to be of diagnostic relevance (26). In the present study, the chipset GSE62165 from the GEO was analyzed, containing data of 118 PDAC and 13 normal pancreatic tissues (11). Differences in gene expression levels were only compared between normal tissues and early-stage tumor tissue. A total of 240 DEGs (137 upregulated and 103 downregulated) were identified using R, and GO (27) and KEGG pathway analyses of DEGs revealed the locations and functions of DEGs. Upregulated genes were mainly located in the ECM and collagen trimers, and were involved in ECM organization and ECM-receptor interactions, focal adhesion, and protein digestion and absorption. Conversely, downregulated genes were mainly enriched in digestion and exopeptidase activity pathways. A PPI network was built, and 18 core genes were identified; the prognostic value of these genes for patients with pancreatic cancer was analyzed using UACLAN. PLAU and COL17A1 were significantly associated with poorer survival; it was then revealed using data from TCGA that COL17A1 was significantly upregulated in pancreatic cancer tissues compared with control tissues, consistent with the results of the differential gene analysis. It was predicted that these two genes may be associated with the proliferation, invasion and metastasis of pancreatic cancer.

PLAU encodes a serine protease, uPA (28). Following GO and KEGG analyses, the functional enrichment of PLAU was investigated. PLAU is mainly involved in the regulation of cell motility, cellular component movement and locomotion (29). It is primarily expressed in the endoplasmic reticulum lumen and invadopodium (30). PLAU plays a key role in regulating cell migration and adhesion during tissue regeneration and intracellular signaling (31). Increased expression of COL17A1 leads to tumor cell invasion and metastasis of tumor cells to surrounding tissues (32). PLAU is involved in predicting the survival rate of patients with gastric cancer (33). It may serve an important role in the invasion and metastasis of pancreatic cancer cells (34); however, the specific pathways involved are yet to be determined. It is hypothesized that PLAU may serve an important role in the diagnosis and treatment of pancreatic cancer in the future.

COL17A1 is mainly located in the extracellular matrix and collagen trimmers (35). Extracellular matrix molecules, including proteoglycan and fibrin, have been reported to affect the growth, migration and differentiation of cells (36). A study showed that COL17A1 can inhibit the migration and invasion of breast cancer cells, acting as a p53 transcriptional target gene (37). A previous study has reported that the extracellular matrix is closely associated with the metastasis of breast cancer (38). High levels of collagen in breast and colorectal cancers have been associated with tumor invasion (39,40). A previous study that employed the minimum-redundancy-maximum-relevance method also identified COL17A1 as a core gene of pancreatic cancer (26); however, in the present study, the upregulated expression of COL17A1 in pancreatic cancer was verified in multiple datasets, and its effects on patient survival were determined. Survival analysis using UACLAN based on data from TCGA revealed that the expression levels of CLO17A1 were closely associated with the survival of patients with pancreatic cancer, and that CLO17A1 was highly expressed in primary pancreatic tumor tissues. The present findings suggested that the expression of COL17A1 is associated with the occurrence and development of pancreatic cancer. Therefore, this bioinformatics analysis may provide novel insight for future studies investigating the pathogenesis of pancreatic cancer.

However, the present study presented certain limitations. In examining the expression level of COL17A1, only four normal samples were investigated, and further studies examining a high number of control samples are required to confirm the present results.

Acknowledgements

Not applicable.

Funding

The present work was supported by The ‘Six Talents Summit’ Project in Jiangsu Province, miR-203 targets Survivin to upregulate the expression of Caspase-3 and promote the apoptosis of pancreatic cancer cells (grant no. WAW-008).

Availability of data and materials

The datasets used and/or analyzed in the present study are available in the GEO (http://www.ncbi.nlm.nih.gov/geo) and UALCAN (http://ualcan.path.uab.edu) repositories.

Authors' contributions

JZ and LX conceived the study. JW, ZL, KW, KZ and DX analyzed the data and drafted the manuscript. All authors reviewed and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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August-2019
Volume 20 Issue 2

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

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Copy and paste a formatted citation
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Spandidos Publications style
Wu J, Li Z, Zeng K, Wu K, Xu D, Zhou J and Xu L: Key genes associated with pancreatic cancer and their association with outcomes: A bioinformatics analysis . Mol Med Rep 20: 1343-1352, 2019
APA
Wu, J., Li, Z., Zeng, K., Wu, K., Xu, D., Zhou, J., & Xu, L. (2019). Key genes associated with pancreatic cancer and their association with outcomes: A bioinformatics analysis . Molecular Medicine Reports, 20, 1343-1352. https://doi.org/10.3892/mmr.2019.10321
MLA
Wu, J., Li, Z., Zeng, K., Wu, K., Xu, D., Zhou, J., Xu, L."Key genes associated with pancreatic cancer and their association with outcomes: A bioinformatics analysis ". Molecular Medicine Reports 20.2 (2019): 1343-1352.
Chicago
Wu, J., Li, Z., Zeng, K., Wu, K., Xu, D., Zhou, J., Xu, L."Key genes associated with pancreatic cancer and their association with outcomes: A bioinformatics analysis ". Molecular Medicine Reports 20, no. 2 (2019): 1343-1352. https://doi.org/10.3892/mmr.2019.10321