Gene networks in basal cell carcinoma of the eyelid, analyzed using gene expression profiling
- Authors:
- Published online on: September 21, 2018 https://doi.org/10.3892/ol.2018.9484
- Pages: 6729-6734
Abstract
Introduction
Basal cell carcinoma (BCC) is the most frequent malignant tumor of the eyelid, and it accounts for ~80% of all malignant eyelid tumors (1,2). Well-known risk factors of BCC include high levels of sunlight exposure and ultraviolet radiation and increasing age (2,3). The progression of BCC is relatively slow, and distant metastasis is rare (4–6). Various treatments have been reported for BCC of the eyelid, including surgical techniques, radiotherapy, cryotherapy, photodynamic therapy, laser ablation, chemotherapy, and immunotherapy (7). However, BCC is topically invasive tumor with destructive growth to surrounding tissue and has a recurrence rate of 1–10% even if appropriate treatment is performed (8). There is limited understanding of how alteration of gene expression in BCC of the eyelid is related to its pathogenesis; therefore, it is important to study the mechanism underlying carcinogenesis at the level of gene profiling.
Several studies have reported gene mutations associated with the carcinogenesis of BCC, such as mutations in the Patched-1 (PTCH1) gene of the sonic hedgehog (SHH) pathway (9) and mutations in the tumor suppressor p53 (10). PTCH-1 suppresses Smoothened signaling and plays an important role in the transcription of cell cycle regulators. p53 is a tumor suppressor gene and prevents gene replication in the case of DNA damage by cell cycle arrest and apoptosis. However, limited information is available at the genetic and molecular levels for BCC of the eyelid, and only a few gene profiling studies have been performed on this disease (11). Therefore, the aim of the current study was to better understand the molecular mechanisms underlying BCC of the eyelid. For this purpose, we analyzed gene expression patterns by using a combination of global microarray analysis and bioinformatics tools.
Patients and methods
Patients and tissue samples
We enrolled two patients, patient 1 (78-year-old woman) and patient 2 (83-year-old woman) with BCC of the eyelid. The patients underwent surgical excision of the tumor at Toyama University Hospital. A part of the tissue samples was frozen and kept at −80°C after sampling for subsequent RNA extraction. The remaining part of the tissue samples was fixed in 4% paraformaldehyde, and paraffin-embedded tissues were stained with hematoxylin-eosin. The study was approved by the institutional review board of the University of Toyama (Toyama, Japan; no. 27–51), and the procedures conformed to the tenets of the World Medical Association's Declaration of Helsinki. Written informed consent was obtained from the patients after they had been provided sufficient information about the procedures.
Cell culture
Normal human epidermal keratinocytes (NHEKs) were obtained from Kurabo Ind., Ltd. (Osaka, Japan; cat. no. KK-4109). They were cultured with HuMedia-KB2 medium (Kurabo Ind., Ltd.) at 37°C in humidified air containing 5% CO2.
RNA isolation
Total RNA was extracted from cancer tissues and NHEKs using a NucleoSpin® RNA isolation kit (Macherey-Nagel GmbH & Co., Düren, Germany) along with On-column DNase I treatment, as per manufacturer instructions. RNA quality was analyzed using a Bioanalyzer 2100 (Agilent Technologies, Inc., Santa Clara, CA, USA).
Microarray gene expression analysis
Microarray gene expression analysis was performed using a GeneChip® system with a Human Genome U133-plus 2.0 array, which was spotted with 54,675 probe sets (Affymetrix, Inc., Santa Clara, CA, USA) according to the manufacturer's instructions.
The hybridization intensity data obtained were converted into a presence or an absence call for each gene, and changes in gene expression levels between experiments were detected by comparison analysis. The data were further analyzed using the GeneSpring® GX software (Agilent Technologies, Inc.) to extract the significant genes. For gene ontology analysis, including that pertaining to biological processes, cellular components, molecular functions, and gene networks, the data obtained were analyzed using Ingenuity® Pathway Analysis tools (Ingenuity Systems, Inc., Mountain View, CA, USA) (12,13).
Results
Histopathological analysis
We performed histopathological examination of surgically removed eyelid tissues from two patients with a lower eyelid mass. We found that the tumor nest composed with small basaloid cell was proliferating with peripheral palisading and mucinous stroma; the histopathological findings were suggestive of BCC of the eyelid (Fig. 1).
Global gene expression analysis
Global gene expression analysis was performed to identify the genes involved in BCC of the eyelid. Complete lists of probe sets for all samples are available on the Gene Expression Omnibus, a public database (accession no. GSE103439). The GeneSpring software was used to analyze gene expression in the two patient samples and the NHEKs and revealed that many genes showed >5.0-fold difference in expression between the two sample types. The Venn diagram in Fig. 2 summarizes the numbers of specifically and commonly expressed genes in each group. The samples from patients 1 and 2 showed upregulation of the expression of 687 and 713 genes, respectively, as compared to that noted in the control cells (NHEKs); 640 genes were upregulated in both patient samples (Fig. 2). From these 640 genes, the upregulated genes that were reported to be associated with BCC are listed as follows: Nkyrin 2 (ANK2), anoctamin 5 (ANO5), androgen receptor (AR), ATPase Na+/K+ transporting subunit α 2 (ATP1A2), BCL2 apoptosis regulator (BCL2), calcium voltage-gated channel auxiliary subunit alpha2delta1 (CACNA2D1), complement factor H (CFH), chromogranin B (CHGB), cardiomyopathy associated 5 (CMYA5), collagen type VI α 3 chain (COL6A3), dihydropyrimidine dehydrogenase (DPYD), fibroblast growth factor receptor 1 (FGFR1), filaggrin (FLG), forkhead box C1 (FOXC1), frizzled class receptor 7 (FZD7), heat shock protein family B member 2 (HSPB2), heat shock protein family B member 3 (HSPB3), heat shock protein family B member 7 (HSPB7), interferon induced transmembrane protein 1 (IFITM1), keratin 1 (KRT1), keratin 4 (KRT4), keratin 7 (KRT7), keratin 13 (KRT13), keratin 19 (KRT19), keratin 23 (KRT23), keratin 25 (KRT25), keratin 79 (KRT79), LIM homeobox 2 (LHX2), LIM and calponin homology domains 1 (LIMCH1), myosin heavy chain (MYH1), nebulin (NEB), nebulin related anchoring protein (NRAP), phosphodiesterase 4D interacting protein (PDE4DIP), PTCH1, SRY-box 9 (SOX9), tropomyosin 2 (TPM2), titin (TTN), tyrosinase related protein 1 (TYRP1) and xin actin binding repeat containing 2 (XIRP2).
Identification of biological functions and gene networks
To identify the biological functions of and the relevant gene networks in the case of genes that were involved in BCC of the eyelid and showed differential expression, functional category and gene network analyses were conducted using the Ingenuity® Pathways Knowledge Base. In the case of the 640 genes that were upregulated in both patient samples, Ingenuity® pathway analysis showed that the gene network included many BCC-associated genes, such as the following (Fig. 3): AR; BCL2; PTCH1; CHGB; heat shock protein 27 (Hsp27); TPM2; NEB; XIRP2; TTN; CACNA2D1; CMYA5; MYH1; and SOX9.
We also identified unique gene networks related to cancer cell growth, tumorigenesis, and cell survival (Fig. 4). The cancer cell growth gene network included several genes, such as the following (Fig. 4A): AR, erb-b2 receptor tyrosine kinase 3 (ERBB3), C-X-C motif chemokine ligand 12 (CXCL12), BCL2, insulin-like growth-factor-binding protein 5 (IGFBP5), matrix metallopeptidase 2 (MMP2), platelet-derived growth factor receptor α (PDGFRA), plasminogen activator, tissue type (PLAT), and prostate stem cell antigen (PSCA). This network was associated with the biological functions involved in cancer cell growth. The tumorigenesis gene network included several genes, such as the following: BCL2, KIT proto-oncogene receptor tyrosine kinase (KIT), CXCL12, serpin family F member 1 (SERPLNF1), insulin-like growth factor 2 (IGF2), IGFBP5, PLAT, and neurotrophic receptor tyrosine kinase 2 (NTRK2). This network was associated with biological functions involved in tumorigenesis (Fig. 4B). The cell survival gene network included several genes, such as the following (Fig. 4C): AR; PSCA; PTCH1; IGF2; fibroblast growth factor receptor 1 (FGFR1); ERBB3; IGFBP5; versican (VCAN); BCL2; and galanin and GMAP prepropeptide (GAL). This network was associated with biological functions involved in cell survival.
Discussion
BCC of the eyelid is the most frequent malignant tumor of the eyelid; however, to date, only insufficient information is available regarding the molecular mechanisms underlying this disease. In the current study, we examined gene expression patterns associated with BCC of the eyelid by performing global microarray analysis, and gene network analysis of differentially expressed genes was performed using computational gene expression analysis tools.
We successfully identified a unique gene network on the basis of our data for upregulated gene expression in patients with BCC of the eyelid. This network included PTCH1 (14,15), which has been reported as an important player in BCC pathogenesis. The PTCH1 gene is a negative regulator of the SHH pathway; the dysfunction of this pathway has been recognized as essential events for BCC development (15,16). Furthermore, it is reported that PTCH-1 mutations contribute to the development of cutaneous eyelid BCC (17). In this network, PTCH1 was found to interact with several genes, such as MYH1, CACNA2D1, AR, SOX9, BCL2, CHGB, Hsp27, TPM2, NEB, NIRP2, TTN, and CMYA5. These genes have been reported to be related to BCC (18–20); it is possible that they play a role at the molecular level in the pathogenesis of BCC of the eyelid. Among them, SOX9 (21,22) and BCL2 (23,24) have been reported as biomarkers of BCC and may play an important role through interactions with PTCH1 in the pathogenesis of this disease.
Our functional category analysis showed that the upregulated genes in patients with BCC of the eyelid were related to biological functions such as cancer cell growth, tumorigenesis, and cell survival (Fig. 4). The cancer cell growth gene network consisted of nine genes, that is, AR (25), BCL2 (26), IGFBP5 (27), CXCL12 (28), ERBB3 (29), MMP2 (30), PDGFRA (31), PLAT (32) and PSCA (33), which have been found to be associated with the cell growth of various cancers, such as renal cell carcinoma, neuroblastoma and pancreatic cancer. The tumorigenesis gene network consisted of 10 genes, that is, PTCH1 (9,34), BCL2 (35), FGFR1 (36), AR (37), ERBB3 (38), IGF2 (39), IGFBP5 (40), PSCA (41), VCAN (42), and GAL (43), which have been reported to be associated with the tumorigenesis of various cancers, such as prostate cancer, neck squamous cell carcinoma and breast cancer. The cell survival gene network consisted of eight genes, that is, BCL2 (44), LGF2 (45), IGFBP5 (46), PLAT (47), NTRK2 (48), SERPINF1 (49), KIT (50), and CXCL12 (50), which have been found to be associated with cell survival in various cancers, such as lung cancer and prostate cancer. In BCC of the eyelid, the genes upregulated in these networks may play an important role in BCC cell survival through the network.
To summarize, from the 640 genes that were upregulated in both patient samples, Ingenuity® pathway analysis showed that the gene network of BCC of the eyelid included many BCC-associated genes, such as BCL2, PTCH1, and SOX9. We identified unique gene networks related with cancer cell growth, tumorigenesis, and cell survival. Thus, our results may help clarify the pathogenesis of BCC of the eyelid at the molecular level. However, the interaction between gene expression and this disease needs to be studied further. These results of integrating microarray analyses provide further insights into the molecular mechanisms involved in BCC of the eyelid and may lead to a therapeutic approach for this disease.
Acknowledgements
Not applicable.
Funding
The present study was supported in part by JSPS KAKENHI (grant no. JP16K20309).
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
Authors' contributions
TY, YT and TH conceived the study, designed the experiments, wrote the manuscript and performed the experiments. SM and JI also performed experiments. TY and AH provided materials for microarray analysis and were involved in data analysis.
Ethics approval and consent to participate
The study was approved by the institutional review board of the University of Toyama (no. 27–51). All patients provided written informed consent.
Patient consent for publication
Written informed consent was obtained from the patients after they were provided with sufficient information about the procedures and publication.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
ANK2 |
ankyrin 2 |
ANO5 |
anoctamin 5 |
AR |
androgen receptor |
ATP1A2 |
ATPase Na+/K+ transporting subunit α 2 |
BCC |
basal cell carcinoma |
BCL2 |
BCL2 apoptosis regulator |
CACNA2D1 |
calcium voltage-gated channel auxiliary subunit alpha2delta1 |
CFH |
complement factor H |
CHGB |
chromogranin B |
CMYA5 |
cardiomyopathy associated 5 |
COL6A3 |
collagen type VI α 3 chain |
CXCL12 |
C-X-C motif chemokine ligand 12 |
DPYD |
dihydropyrimidine dehydrogenase |
ERBB3 |
erb-b2 receptor tyrosine kinase 3 |
FGFR1 |
fibroblast growth factor receptor 1 |
FLG |
filaggrin |
FOXC1 |
forkhead box C1 |
FZD7 |
frizzled class receptor 7 |
GAL |
galanin and GMAP prepropeptide |
Hsp27 |
heat shock protein 27 |
HSPB2 |
heat shock protein family B member 2 |
HSPB3 |
heat shock protein family B member 3 |
HSPB7 |
heat shock protein family B member 7 |
IFITM1 |
interferon induced transmembrane protein 1 |
IGF2 |
insulin like growth factor 2 |
IGFBP5 |
insulin like growth factor binding protein 5 |
KIT |
KIT proto-oncogene receptor tyrosine kinase |
KRT1 |
keratin 1 |
KRT4 |
keratin 4 |
KRT7 |
keratin 7 |
KRT13 |
keratin 13 |
KRT19 |
keratin 19 |
KRT23 |
keratin 23 |
KRT25 |
keratin 25 |
KRT79 |
keratin 79 |
LHX2 |
LIM homeobox 2 |
LIMCH1 |
LIM and calponin homology domains 1 |
MMP2 |
matrix metallopeptidase 2 |
MYH1 |
myosin heavy chain 1 |
NEB |
nebulin |
NHEK |
normal human epidermal keratinocytes |
NRAP |
nebulin related anchoring protein |
NTRK2 |
neurotrophic receptor tyrosine kinase 2 |
PDE4DIP |
phosphodiesterase 4D interacting protein |
PDGFRA |
platelet-derived growth factor receptor α |
PLAT |
plasminogen activator, tissue type |
PSCA |
prostate stem cell antigen |
PTCH1 |
Patched-1 |
SERPINF1 |
serpin family F member 1 |
SHH |
sonic hedgehog |
SOX9 |
SRY-box 9 |
TPM2 |
tropomyosin 2 |
TTN |
titin |
TYRP1 |
tyrosinase related protein 1 |
VCAN |
versican |
XIRP2 |
xin actin binding repeat containing 2 |
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