Citation: Shihori Tanabe, Kazuhiko Aoyagi, Hiroshi Yokozaki, Hiroki Sasaki. Molecular pathway network of EFNA1 in cancer and mesenchymal stem cells[J]. AIMS Cell and Tissue Engineering, 2018, 2(2): 58-77. doi: 10.3934/celltissue.2018.2.58
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The signaling network moves dynamically in stem cells and cancer. An alteration in the gene expression of molecules drives the signaling network pattern transition. The molecular pattern changes upon cellular stimuli or cellular phenotype transition. Among the abundant molecule-related cancer and stem cell signaling pathways, the membrane protein is an entrance for the intracellular pathway cascade. Ephrin A1 (EFNA1) encodes a member of the ephrins (Eph receptor interacting proteins), which functions as a ligand for the Eph (erythropoietin-producing hepatocellular carcinoma) receptor protein-tyrosine kinase family [1,2,3,4]. EFNA1 binds to the EPHA2, EPHA4, EPHA5, EPHA6 and EPHA7 receptors in vitro and selectively binds to EPHA4 but not EPHA7 in the lysates of rat striatal tissue [5,6,7,8,9].
EPH/ephrin signaling is involved in many cellular functions such as cell proliferation and cell cycle progression, and it is suggested to play a role even in cancer stem cells (CSCs) [2]. EFNA1 is up-regulated in melanoma progression [10]. The EFNA1 and EPHA2 axis is implicated in gastric cancer (GC) [11]. EPHA2 expression is a poor prognostic marker in stage II/III colorectal cancer [5]. The EPHA2 and EFNA1 signaling system leads to an increase in the migration and invasion of solid tumors [12]. In contrast, EPHA1 is suggested to be a tumor suppressor [13]. Ephrins and EPHAs are induced in stem cells and regulate myogenic progression [14]. We have previously demonstrated that the epithelial-mesenchymal transition (EMT) network includes EFNA1 [15]. Since EPH/ephrin signaling is important for cancer, we investigated the EFNA1 gene expression and network pathway related to EMT in diffuse-type GC and mesenchymal stem cells (MSCs). EMT plays a role in cancer metastasis and malignancy, which is a critical phenotype of cancer stem cells (CSCs). Diffuse-type GC exhibits the EMT-like feature compared to the intestinal-type GC, which may contribute to CSC phenotype. We investigated the gene expression profiling in MSCs and diffuse-type GC, since the regulated genes in diffuse-type GC may contain the molecules related to malignancy or CSCs. To elucidate the EFNA1 role in EMT mechanism associated with cancer and stem cells, we compared EFNA1 gene expression in MSCs and diffuse-type GC.
The human bone marrow MSCs were commercially available (Lonza, Walkersville, MD, USA) and cultured in MSC growth medium (MSCGM; Lonza #PT-3001; MSC basal medium supplemented with mesenchymal cell growth supplement, L-glutamine and penicillin/streptomycin) at 37°C in a CO2 (5%) incubator as previously described [15]. The diffuse-type GC tissues were provided by the National Cancer Center Hospital in Japan after obtaining written informed consent from each patient and approval from the National Cancer Center Institutional Review Board, and total RNA was obtained from the frozen sample [16].
The gene expression in MSCs (n = 12) and diffuse-type GC (n = 5) was analyzed with GeneChip® Human Genome U133 Plus 2.0 microarray (Affymetrix, Santa Clara, California, USA), as previously described [15,16,17]. Briefly, total RNA purified from the cells were biotinylated and hybridized to the microarray. The signal intensity in each gene was analyzed and compared between MSCs and diffuse-type GC. The microarray data for MSCs and diffuse-type GC are available to the public in NCBI's Gene Expression Omnibus (GEO) database and are accessible via GEO Series accession number GSE7888 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE7888) and GSE42252 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE42252), respectively [15,16,17].
The cancer genomics data analysis related to EFNA1 was performed using the cBioPortal for Cancer Genomics (http://www.cbioportal.org) [18,19]. The term “EFNA1” was searched in the cBioPortal for Cancer Genomics, and the cross-cancer alteration summary for EFNA1 was obtained. The network pathway analysis of EFNA1 using the cBioPortal for Cancer Genomics (http://www.cbioportal.org) showed the cross-cancer alteration and EFNA1-associated network. The EFNA1 molecular network was analyzed in stomach adenocarcinoma (TCGA, Nature 2014, tumor samples with sequencing and CNA data, 287 samples/1 gene) [20].
Gene Ontology of EFNA1 was analyzed using several databases, including the EMBL-EBI (http://www.ebi.ac.uk/QuickGO/), AmiGO 2 (http://amigo.geneontology.org/amigo/landing) and the Gene Ontology Consortium (http://geneontology.org/).
Pathway network analysis was performed using the databases VaProS (http://pford.info/vapros/), Kyoto Encyclopedia of Genes and Genomes (KEGG) (http://www.genome.jp/kegg/), cBioPortal for Cancer Genomics (http://www.cbioportal.org), and Cytoscape (http://www.cytoscape.org/). The localization of molecules was analyzed using The Human Protein Atlas (http://www.proteinatlas.org/) [21] and UniProt (http://www.uniprot.org/). Molecular interactions were analyzed using the BioGRID (http://www.thebiogrid.org) database.
The data were expressed as the mean ± SE. For the statistics, Student's t-test in each probe sets was performed in Microsoft® Excel®. p < 0.05, 0.01 or 0.001 (n = 12 in MSCs, n = 5 in GC) was considered as statistically significant.
The gene expression of EFNA1 was up-regulated in diffuse-type GC compared to MSCs (Figure 1). The gene expression of EPHA2, a receptor for EFNA1, was up-regulated in some samples of diffuse-type GC compared to MSCs (Figure 2A, B). The gene expression of EPHA7 was differentially up-regulated in diffuse-type GC compared to MSCs (Figure 2C, D). The data are expressed as the means ± SE. In case significantly different, p value calculated with Student's t-test is shown in Figure legends.
Figure 1. Gene expression of EFNA1 in MSCs and diffuse-type GC.A: Microarray analysis revealed that gene expression of EFNA1 was up-regulated in diffuse-type GC compared to MSCs (a p < 0.001 in Student's t-test, n = 12 in MSCs, n = 5 in diffuse-type GC). B: The signal intensity in each samples of MSCs and diffuse-type GC are shown.
Figure 2. Gene expression of EPHAs in MSCs and diffuse-type GC.A: EPHA2 gene expression in MSCs and diffuse-type GC is shown. B: EPHA2 gene expression in each sample of MSCs and diffuse-type GC is shown. C: EPHA7 gene expression in MSCs and diffuse-type GC is shown. D: EPHA7 gene expression in each sample of MSCs and diffuse-type GC is shown (b p < 0.01 in Student's t-test, n = 12 in MSCs, n = 5 in diffuse-type GC).
According to the KEGG pathway, pathways of EFNA1 are the Ras signaling pathway, Rap1 signaling pathway, PI3K-Akt signaling pathway and axon guidance. The Gene Ontology (GO) of EFNA1 includes cell migration, cell-cell signaling, ephrin receptor binding, ephrin receptor signaling pathway, and negative regulation of EMT (Table 1) (http://amigo.geneontology.org/amigo/gene_product/UniProtKB:P20827).
| GO class (direct) | Evidence |
| anchored component of plasma membrane | IBA |
| angiogenesis | IBA |
| aortic valve morphogenesis | ISS |
| axon guidance | IBA |
| cell migration | IDA |
| cell-cell signaling | TAS |
| endocardial cushion to mesenchymal transition involved in heart valve formation | ISS |
| ephrin receptor binding | IBA, IPI |
| ephrin receptor signaling pathway | IBA, IDA, IGI, TAS |
| extracellular region | IEA |
| integral component of plasma membrane | TAS |
| mitral valve morphogenesis | ISS |
| negative regulation of dendritic spine morphogenesis | ISS |
| negative regulation of epithelial to mesenchymal transition | ISS |
| negative regulation of MAPK cascade | IEA |
| negative regulation of proteolysis involved in cellular protein catabolic process | IGI |
| negative regulation of thymocyte apoptotic process | IEA |
| negative regulation of transcription by RNA polymerase II | ISS |
| notochord formation | IEA |
| plasma membrane | IBA, NAS, TAS |
| positive regulation of amyloid-beta formation | IDA |
| positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process | IGI |
| positive regulation of MAPK cascade | IEA |
| positive regulation of peptidyl-tyrosine phosphorylation | IDA |
| positive regulation of protein phosphorylation | IGI |
| GO class (direct) | Evidence |
| positive regulation of protein tyrosine kinase activity | IGI |
| protein binding | IPI |
| protein stabilization | IGI |
| regulation of angiogenesis | IEA |
| regulation of axonogenesis | IEA |
| regulation of blood vessel endothelial cell migration | IEA |
| regulation of cell adhesion mediated by integrin | IDA |
| regulation of peptidyl-tyrosine phosphorylation | ISS |
| signaling receptor binding | TAS |
| substrate adhesion-dependent cell spreading | IDA |
| IBA: Inferred from Biological Ancestry, IDA: Inferred from Direct Assay, IEA: Inferred from Electronic Annotation, IGI: Inferred from Genetic Interaction, IPI: Inferred from Physical Interaction, ISS: Inferred from Sequence or structural Similarity, NAS: Non-traceable Author Statement, TAS: Traceable Author Statement. | |
DownLoad: CSVThe enrichment analysis of EFNA1 using the cBioPortal for Cancer Genomics revealed mRNA expression alteration of SCARNA2 and ZFAND1 in EFNA1-altered cases and EFNA1-unaltered cases in stomach adenocarcinoma (TCGA, Nature 2014) (Table 2) [20].
| Gene | Cytoband | Mean mRNA expression (Altered) | Mean mRNA expression (Unaltered) | Standard deviation of mRNA expression (Altered) | Standard deviation of mRNA expression (Unaltered) | p-Value | q-Value |
| SCARNA2 | 1q13.1 | 3.7 | 2.44 | 0.26 | 1.43 | 5.65E−09 | 8.17E−05 |
| ZFAND1 | 8q21.13 | 3.46 | 4.11 | 0.19 | 0.68 | 6.17E−06 | 0.0446 |
| NGEF | 2q37 | 2.62 | 1.25 | 0.44 | 1.66 | 1.75E−05 | 0.0845 |
| PTAFR | 1p35−p34.3 | 2.13 | 2.54 | 0.15 | 1.05 | 4.18E−05 | 0.151 |
| STK17A | 7p13 | 2.54 | 2.91 | 0.14 | 0.54 | 9.73E−05 | 0.282 |
| CHI3L1 | 1q32.1 | 1.63 | 2.83 | 0.49 | 2.09 | 1.22E−04 | 0.295 |
| CEP120 | 5q23.2 | 1.62 | 2.25 | 0.25 | 0.6 | 2.99E−04 | 0.552 |
| TPD52L1 | 6q22−q23 | 2.38 | 0.92 | 0.64 | 2.11 | 3.48E−04 | 0.552 |
| ZNF232 | 17p13.2 | 0.95 | 1.4 | 0.2 | 0.62 | 3.82E−04 | 0.552 |
| IGSF9 | 1q22−q23 | 2.97 | 1.53 | 0.64 | 1.86 | 4.08E−04 | 0.552 |
| CDH13 | 16q23.3 | 0.98 | 1.93 | 0.42 | 1.06 | 4.66E−04 | 0.552 |
| RMDN1 | 8q21.3 | 3.15 | 3.56 | 0.19 | 0.56 | 5.06E−04 | 0.552 |
| PAPD4 | 5q14.1 | 3.07 | 3.6 | 0.23 | 0.48 | 5.95E−04 | 0.552 |
| GPR35 | 2q37.3 | 4.76 | 4.08 | 0.33 | 1.42 | 6.08E−04 | 0.552 |
| C1ORF54 | 1q21.2 | 2.06 | 3.07 | 0.45 | 0.9 | 6.71E−04 | 0.552 |
| CSNK1G3 | 5q23 | 2.43 | 2.89 | 0.21 | 0.53 | 6.74E−04 | 0.552 |
| FGF11 | 17p13.1 | −1.56 | −0.48 | 0.51 | 1.33 | 7.10E−04 | 0.552 |
| CAMK2N2 | 3q27.1 | −1.45 | −0.32 | 0.55 | 1.84 | 7.19E−04 | 0.552 |
| CSNK1A1 | 5q32 | 4.36 | 4.8 | 0.2 | 0.4 | 7.51E−04 | 0.552 |
| CREBL2 | 12p13 | 3.29 | 3.83 | 0.25 | 0.57 | 7.74E−04 | 0.552 |
| CORO2A | 9q22.3 | 3.66 | 2.87 | 0.38 | 1.21 | 8.06E−04 | 0.552 |
| UGT8 | 4q26 | 3.44 | 2.26 | 0.59 | 2.02 | 8.62E−04 | 0.552 |
| ZSCAN32 | 16p13.3 | 1.29 | 1.88 | 0.27 | 0.44 | 9.04E−04 | 0.552 |
| DNAJC22 | 12q13.12 | 3.23 | 2.4 | 0.42 | 1.71 | 9.16E−04 | 0.552 |
DownLoad: CSVA model network of EFNA1 is shown in Figure 3. Primary localization information was based on the Cell Atlas in the Human Protein Atlas where available, and secondary localization information was based on subcellular location information in the UniProt database. Among the genes in the network generated with cBioPortal, the up-regulated (UR) genes in GC compared to MSCs are shown in pink, whereas down-regulated (DR) genes are shown in blue. Genes showing a fold change (FC) greater than 3 with a p value less than 0.01 are shown without highlight. The genes in which the FC of gene expression is between 2 and 3 and the p value is less than 0.01 are highlighted in light beige.
Figure 3. The EFNA1 model network.The EFNA1 model network is shown. The localization of molecules was analyzed with The Human Protein Atlas (http://www.proteinatlas.org/) and UniProt (http://www.uniprot.org/).
The interaction of EFNA1 was analyzed using the BioGRID database (Table 3). The interactors of EFNA1 included pro-platelet basic protein (PPBP), eukaryotic translation elongation factor 1 gamma (EEF1G), lysine acetyltransferase 5 (KAT5), EPH receptor A4 (EPHA4), EPH receptor A3 (EPHA3), and X-ray repair cross complementing 6 (XRCC6). EFNA1 had 7 published interactions and 6 interactors [22,23,24,25].
| Official Symbol | Entrez Gene | Pubmed ID |
| PPBP | 5473 | 16169070, 21900206 |
| EEF1G | 1937 | 16169070 |
| KAT5 | 10524 | 16169070 |
| EPHA4 | 2043 | 10366629 |
| EPHA3 | 2042 | 9195962 |
| XRCC6 | 2547 | 21900206 |
DownLoad: CSVTo reveal the molecular network in CSCs, 30 genes involved in CSCs were queried in the cBioPortal for Cancer Genomics, and the network was analyzed in stomach adenocarcinoma (TCGA, Nature 2014, tumor samples with sequencing and CNA data, 287 samples/30 genes) [20] (Figure 4A, B). The network contained 80 nodes, including 30 queried genes and the 50 most frequently altered neighbor genes (out of a total of 131 genes). In the network shown in Figure 4A, 16 core genes are marked with bold circles, and a total of 61 genes are mapped. The gene expression and localization information of core genes and adjacent genes are summarized in Figure 4B and Table 4. The node colored in pink indicates UR genes, and the node colored in blue indicates DR genes.
Figure 4. The cancer stem cell model network.A: The cancer stem cell (CSC) model network was generated using the cBioPortal for Cancer Genomics. A total of 30 genes involved in CSCs were queried in the cBioPortal Cancer Genomics, and the network was analyzed in stomach adenocarcinoma (TCGA, Nature 2014, tumor samples with sequencing and CNA data, 287 samples / 30 genes). B: The CSC model network is shown. Molecules were mapped with the localization information based on The Human Protein Atlas (http://www.proteinatlas.org/) and UniProt (http://www.uniprot.org/).
| Gene symbol | Full name | Ratio in diffuse-type GC to MSC (GAPDH normalized) | Localization (The human protein atlas, supported) | Localization (UniProt) |
| BMI1 /// COMMD3-BMI1 | BMI1 proto-oncogene, polycomb ring finger /// COMMD3-BMI1 readthrough | 1.76 | Localized to the Nucleus (approved), Nuclear bodies (approved) | Nucleus Cytoplasm |
| CXCR4 | C-X-C motif chemokine receptor 4 | 1901.94 | Not available | Cell membrane; Multi-pass membrane protein; Cell junction; Early endosome; Late endosome; Lysosome |
| EFNA1 | ephrin A1 | 216.27 | Not available | Cell membrane; Lipid-anchor 〉 GPI-anchor; Secreted |
| EFNB2 | ephrin B2 | 2.87 | Localized to the Nucleoplasm (supported) | Membrane |
| EPHA5 | EPH receptor A5 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein; Cell projection 〉 axon; Cell projection 〉 dendrite |
| ERBB2 | erb-b2 receptor tyrosine kinase 2 | 3.04 | Localized to the Plasma membrane (supported) In addition localized to the Cytosol (supported) |
Isoform 1: Cell membrane; Single-pass type I membrane protein; Cytoplasm 〉 perinuclear region; Nucleus; Isoform 2 & 3: Cytoplasm; Nucleus |
| ITGB1 | integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) | 0.31 | Localized to the Plasma membrane (supported), Focal adhesion sites (supported) | Cell membrane; Single-pass type I membrane protein; Cell projection 〉 invadopodium membrane; Single-pass type I membrane protein; Cell projection 〉 ruffle membrane; Single-pass type I membrane protein; Recycling endosome; Melanosome; Cleavage furrow; Cell projection 〉 lamellipodium; Cell projection 〉 ruffle; Cell junction 〉 focal adhesion; Cell surface |
| NANOG | Nanog homeobox | Signal intensity is low | Not available | Nucleus |
| NOTCH1 | notch 1 | 6.94 | Localized to the Nucleoplasm (approved) | Cell membrane; Single-pass type I membrane protein |
| POU5F1 | POU class 5 homeobox 1 | Signal intensity is low | Localized to the Nucleoplasm (supported) In addition localized to the Cytosol (supported) |
Cytoplasm Nucleus |
| RUNX2 | runt related transcription factor 2 | 0.79 | Localized to the Nucleoplasm (validated) | Nucleus |
| SFRP1 | Secreted frizzled-related protein 1 | 5.22 | Nucleoli (approved) | Secreted |
| SHH | sonic hedgehog | Signal intensity is low | Not available | Sonic hedgehog protein C-product: Secreted 〉 extracellular space; Sonic hedgehog protein N-product: Cell membrane; Lipid-anchor |
| SNAI1 | snail family transcriptional repressor 1 | Signal intensity is low | Localized to the Nucleus (supported), Cytosol (supported) | Nucleus Cytoplasm |
| SNAI2 | snail family transcriptional repressor 2 | 0.30 | Localized to the Nucleus (approved) | Nucleus Cytoplasm |
| SOX2 | SRY-box 2 | 47.16 | Localized to the Nucleoplasm (supported) | Nucleus |
| APC | APC, WNT signaling pathway regulator | 1.03 | Not available | Cell junction 〉 adherens junction; Cytoplasm 〉 cytoskeleton; Cell projection 〉 lamellipodium; Cell projection 〉 ruffle membrane; Cytoplasm; Cell membrane |
| CDH1 | cadherin 1 | 228.47 | Localized to the Plasma membrane (supported), Cell Junctions (supported) In addition localized to the Golgi apparatus (supported) |
Cell junction; Cell membrane; Single-pass type I membrane protein; Endosome; Golgi apparatus 〉 trans-Golgi network |
| CDH10 | cadherin 10 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDH12 | cadherin 12 | Signal intensity is low | Localized to the Vesicles (approved) | Cell membrane; Single-pass type I membrane protein |
| CDH18 | cadherin 18 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDH23 | cadherin 23 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDH4 | cadherin 4 | Signal intensity is low | Localized to the Plasma membrane (validated) | Cell membrane; Single-pass type I membrane protein |
| CDH9 | cadherin 9 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDKN2A | cyclin dependent kinase inhibitor 2A | 0.23 | Localized to the Nucleoli (validated) | Cytoplasm Nucleus |
| CELSR1 | cadherin, EGF LAG seven-pass G-type receptor 1 (flamingo homolog, Drosophila) | Signal intensity is low | Localized to the Plasma membrane (supported) | Cell membrane; Multi-pass membrane protein |
| CELSR3 | cadherin EGF LAG seven-pass G-type receptor 3 | Signal intensity is low | Not available | Cell membrane; Multi-pass membrane protein |
| CNTN6 | contactin 6 | Signal intensity is low | Not available | Cell membrane; Lipid-anchor 〉 GPI-anchor |
| COL12A1 | collagen type XII alpha 1 chain | 0.14 | Localized to the Nucleus (approved) | Secreted 〉 extracellular space 〉 extracellular matrix |
| COL14A1 | collagen type XIV alpha 1 chain | 1.59 | Localized to the Vesicles (approved) | Secreted 〉 extracellular space 〉 extracellular matrix |
| COL20A1 | collagen type XX alpha 1 chain | Signal intensity is low | Not available | Secreted 〉 extracellular space |
| CREBBP | CREB binding protein | 1.89 | Localized to the Nucleoplasm (validated) In addition localized to the Nuclear bodies (validated) |
Cytoplasm Nucleus |
| CUX1 | cut-like homeobox 1 | 3.87 | Localized to the Nucleoplasm (supported), Golgi apparatus (supported) | Nucleus |
| DCC | deleted in colorectal carcinoma | Signal intensity is low | Localized to the Golgi apparatus (approved) | Membrane; Single-pass type I membrane protein |
| EGFR | epidermal growth factor receptor | 2.08 | Localized to the Plasma membrane (validated) | Cell membrane; Single-pass type I membrane protein Endoplasmic reticulum membrane; Single-pass type I membrane protein Golgi apparatus membrane; Single-pass type I membrane protein Nucleus membrane; Single-pass type I membrane protein Endosome; Endosome membrane Nucleus |
| ERBB3 | erb-b2 receptor tyrosine kinase 3 | 167.50 | Localized to the Actin filaments (approved) In addition localized to the Plasma membrane (supported) |
Isoform 1: Cell membrane; Single-pass type I membrane protein Isoform 2: Secreted |
| ERBB4 | erb-b2 receptor tyrosine kinase 4 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| FAT1 | FAT atypical cadherin 1 | 0.88 | Not available | Cell membrane; Single-pass type I membrane protein Nucleus Cytoplasm 〉 perinuclear region |
| FAT2 | FAT atypical cadherin 2 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein Cell junction Nucleus |
| FAT3 | FAT atypical cadherin 3 | Signal intensity is low | Not available | Membrane; Single-pass type I membrane protein |
| FBN1 | fibrillin 1 | 0.20 | Localized to the Cytosol (approved) | Secreted |
| FBXW7 | F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase | 2.53 | Localized to the Nucleoplasm (supported) In addition localized to the Vesicles (approved) |
Isoform 1: Nucleus 〉 nucleoplasm Isoform 2: Cytoplasm Isoform 3: Nucleus 〉 nucleolus |
| FLNA | filamin A | 1.45 | Localized to the Plasma membrane (validated), Actin filaments (validated), Cytosol (validated) | Cytoplasm 〉 cell cortex Cytoplasm 〉 cytoskeleton |
| GLI3 | GLI family zinc finger 3 | 1.34 | Not available | Nucleus; Cytoplasm; Cell projection 〉 cilium |
| GRB7 | growth factor receptor-bound protein 7 | Signal intensity is low | Localized to the Plasma membrane (supported) | Cytoplasm; Cell junction 〉 focal adhesion; Cell membrane; Peripheral membrane protein; Cytoplasmic side; Cytoplasmic granule Cell projection |
| HSPG2 | heparan sulfate proteoglycan 2 | 1.29 | Localized to the Nucleoplasm (approved), Plasma membrane (approved), Cytosol (approved) | Secreted 〉 extracellular space 〉 extracellular matrix 〉 basement membrane |
| KRAS | KRAS proto-oncogene, GTPase | 1.75 | Not available | Cell membrane; Lipid-anchor; Cytoplasmic side Cytoplasm 〉 cytosol |
| LRP2 | low density lipoprotein receptor-related protein 2 | Signal intensity is low | Localized to the Vesicles (approved), Mitochondria (approved) | Membrane; Single-pass type I membrane protein Membrane 〉 coated pit |
| MYC | v-myc myelocytomatosis viral oncogene homolog (avian) | 2.85 | Localized to the Nucleoplasm (validated) | Nucleus 〉 nucleoplasm Nucleus 〉 nucleolus |
| NFATC2 | nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 | 27.85 | Localized to the Nucleoplasm (supported), Cytosol (supported) | Cytoplasm Nucleus |
| PCDH10 | protocadherin 10 | 0.07 | Localized to the Golgi apparatus (approved) In addition localized to the Nucleus (approved), Vesicles (approved) |
Cell membrane; Single-pass type I membrane protein |
| PCDH15 | protocadherin-related 15 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein Isoform 3 :Secreted |
| PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | 1.33 | Localized to the Cytosol (approved) | GO - Cellular component cytosol Source: Reactome lamellipodium Source: Ensembl phosphatidylinositol 3-kinase complex Source: BHF-UCL phosphatidylinositol 3-kinase complex, class IA Source: UniProtKB plasma membrane Source: GO_Central |
| PSME4 | proteasome (prosome, macropain) activator subunit 4 | 1.97 | Localized to the Nucleoplasm (supported) | Cytoplasm 〉 cytosol Nucleus Nucleus speckle |
| PTEN | phosphatase and tensin homolog | 15.55 | Localized to the Nucleoplasm (supported) In addition localized to the Cytosol (supported) |
Cytoplasm Nucleus Nucleus 〉 PML body Isoform alpha: Secreted |
| RELN | reelin | Signal intensity is low | Localized to the Focal adhesion sites (approved) In addition localized to the Plasma membrane (approved) |
Secreted 〉 extracellular space 〉 extracellular matrix |
| SALL4 | sal-like 4 (Drosophila) | Signal intensity is low | Localized to the Nucleoplasm (validated) | Cytoplasm Nucleus |
| SMAD4 | SMAD family member 4 | 2.32 | Localized to the Nucleoplasm (supported), Cytosol (supported) In addition localized to the Centrosome (approved) |
Cytoplasm Nucleus |
| SPTA1 | spectrin, alpha, erythrocytic 1 (elliptocytosis 2) | Signal intensity is low | Not available | Cytoplasm 〉 cytoskeleton Cytoplasm 〉 cell cortex |
| TP53 | tumor protein p53 | Signal intensity is low | Localized to the Nucleoplasm (validated) | Cytoplasm Nucleus Nucleus 〉 PML body Endoplasmic reticulum Mitochondrion matrix |
| TRIO | triple functional domain (PTPRF interacting) | 0.92 | Localized to the Cytosol (approved) In addition localized to the Vesicles (approved) |
Cytoplasm |
DownLoad: CSVThe EFN/EPH signaling pathway is important for cancer. In the case of medulloblastoma, ephrinB1 is differentially expressed and mainly expressed in islands within the tumor comprised of dense neoplastic cells with a high mitotic proliferative index [26]. It has been reported that EphA2 is regulated by E-cadherin (CDH1 or cadherin 1) [27]. E-cadherin loss in breast cancer leads to a decrease in phosphorylated EphA2 and altered neoplastic cell growth and adhesion [27]. Single nucleotide polymorphisms (SNPs) in the EFNA1 gene have been found to play an important role in GC susceptibility [28]. The results of an Identify Candidate Causal SNPs and Pathways (ICSNPathway) analysis using a GC genome-wide association study (GWAS) dataset indicated that SNPs rs4745 and rs12904 lead to an EFNA1 and ephrin receptor binding pathway in GC [28,29]. These SNPs, rs4745 and rs12904, are suggested to affect the regulatory roles in the ephrin receptor binding of EFNA1 [30]. Considering that the overexpression of EFNA1 is observed in 57% of GC tissue samples, the EFNA1 and EPH pathway may play a crucial role in GC [11].
The present study revealed that the EFNA1 was up-regulated in diffuse-type GC compared to MSCs. It has been described that the EFNA1 is up-regulated in GC in the previous studies [11,31], which shows the consistency of the present study with the previous findings. The present study demonstrated the novel EFNA1 network model showing the gene expression patterns in diffuse-type GC and MSCs. This EFNA1 molecular network contains EMT-related molecules such as CDH1 (E-cadherin) and CTNNB1 (β-catenin). The EFNA1 network also contains AKT signaling molecules and PTEN which are up-regulated in diffuse-type GC compared to MSCs. The generated EFNA1 network contains the molecules such as KRAS, SLIT2, APC and RAC1, although their gene expression were not altered in diffuse-type GC and MSCs. The up-regulated genes may include the important molecules for CSCs.
EFN/EPH signaling pathway networks and the Wnt/β-catenin signaling pathway are suggested to interact with each other [32]. EFNB1 mRNA is expressed in human embryonic stem (ES) cells and diffuse-type GC. EFNB3 has been identified as a potential transcriptional target of the Wnt/β-catenin signaling pathway [32]. The Wnt/β-catenin signaling pathway is implicated in GC and the self-renewal of stem cells, which suggests that the Wnt/β-catenin signaling pathway may be an interesting target for the investigation of CSCs in GC. EPH receptor tyrosine kinases are implicated in CSC regulation [33]. β-catenin accumulates in the nucleus of cells at the bottom of the small intestine crypts of EphB2−/−EphB3−/− mice, which suggests cross-talk between β-catenin signaling and EFN/EPH signaling [34].
The gene expression of EPHA2 and EPHA7 had tendency to be up-regulated in diffuse-type GC compared to MSCs. It has been reported that the gene expression pattern of EPHA2, EFNA1 and EGFR is significantly associated with poor response to treatment with cetuximab, an anti-EGFR antibody, in stage IV colorectal cancer, which suggests that the EGFR signaling pathway and EFN/EPH signaling pathway cross-talk in cancer cells [35]. A study that is involved in gene expression profiling of muscle stem cells has demonstrated that EphA1, EphA2, EfnA1, and EphB1 were induced, whereas EphA3, EphA4, EphA7, EfnA2, EfnA3, EfnA4, EfnA5, EphB2, EphB3, EphB4, EfnB1, EfnB2 and EfnB3 were inhibited during postnatal myogenesis in mice [36]. In glioblastoma, EphA2 was overexpressed in stem cells, and the Akt signaling pathway experienced cross-talk with EphA2 to regulate stem cell properties [37]. Hepatic progenitor cell markers include EFNA1, EpCAM, CK7 (KRT7), CK19 (KRT19), alpha-fetoprotein (AFP) and CD90 (THY1) [38]. These results demonstrate that the EFN/EPH signaling pathway is regulated in stem cell differentiation.
In conclusion, EFNA1 was up-regulated in diffuse-type GC compared to MSCs, and the network pathway analysis demonstrated that EFNA1 model network contains EMT-related molecules. The CSC model network was also generated, in which CSC-related genes such as EGFR, ERBB2, and NOTCH1 are included. To reveal the EMT and CSC mechanism, the expression analysis of network molecules in several types of cancer would be for the future investigation.
We appreciate all who were involved in the research. We gratefully acknowledge Dr Ryoji Kushima for the pathological and clinical evaluations. We would also like to thank Ms. Rie Komatsuzaki and Ms. Fumiko Chiwaki for their technical assistance. This study was supported in part by the National Institute of Biomedical Innovation, the Ministry of Health, Labour and Welfare of Japan, National Cancer Center Research and Development Fund, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Princess Takamatsu Cancer Research Fund. The authors would like to thank Dr. Akihiko Hirose and Dr. Takashi Yamada for supporting in the preparation of the manuscript. The authors would like to thank Prof. Kei Yura for introducing us to the VaProS database. This research in part used VaProS, a data-cloud developed by the Information Core of the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Drug Discovery, Informatics, and Structural Life Science) from the Japan Agency for Medical Research and Development (AMED).
The author declares that no conflicts of interest exist.
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| 1. | Shihori Tanabe, Sabina Quader, Horacio Cabral, Ryuichi Ono, Interplay of EMT and CSC in Cancer and the Potential Therapeutic Strategies, 2020, 11, 1663-9812, 10.3389/fphar.2020.00904 | |
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Shihori Tanabe, Kazuhiko Aoyagi, Hiroshi Yokozaki, Hiroki Sasaki. Molecular pathway network of EFNA1 in cancer and mesenchymal stem cells[J]. AIMS Cell and Tissue Engineering, 2018, 2(2): 58-77. doi: 10.3934/celltissue.2018.2.58
| GO class (direct) | Evidence |
| anchored component of plasma membrane | IBA |
| angiogenesis | IBA |
| aortic valve morphogenesis | ISS |
| axon guidance | IBA |
| cell migration | IDA |
| cell-cell signaling | TAS |
| endocardial cushion to mesenchymal transition involved in heart valve formation | ISS |
| ephrin receptor binding | IBA, IPI |
| ephrin receptor signaling pathway | IBA, IDA, IGI, TAS |
| extracellular region | IEA |
| integral component of plasma membrane | TAS |
| mitral valve morphogenesis | ISS |
| negative regulation of dendritic spine morphogenesis | ISS |
| negative regulation of epithelial to mesenchymal transition | ISS |
| negative regulation of MAPK cascade | IEA |
| negative regulation of proteolysis involved in cellular protein catabolic process | IGI |
| negative regulation of thymocyte apoptotic process | IEA |
| negative regulation of transcription by RNA polymerase II | ISS |
| notochord formation | IEA |
| plasma membrane | IBA, NAS, TAS |
| positive regulation of amyloid-beta formation | IDA |
| positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process | IGI |
| positive regulation of MAPK cascade | IEA |
| positive regulation of peptidyl-tyrosine phosphorylation | IDA |
| positive regulation of protein phosphorylation | IGI |
| GO class (direct) | Evidence |
| positive regulation of protein tyrosine kinase activity | IGI |
| protein binding | IPI |
| protein stabilization | IGI |
| regulation of angiogenesis | IEA |
| regulation of axonogenesis | IEA |
| regulation of blood vessel endothelial cell migration | IEA |
| regulation of cell adhesion mediated by integrin | IDA |
| regulation of peptidyl-tyrosine phosphorylation | ISS |
| signaling receptor binding | TAS |
| substrate adhesion-dependent cell spreading | IDA |
| IBA: Inferred from Biological Ancestry, IDA: Inferred from Direct Assay, IEA: Inferred from Electronic Annotation, IGI: Inferred from Genetic Interaction, IPI: Inferred from Physical Interaction, ISS: Inferred from Sequence or structural Similarity, NAS: Non-traceable Author Statement, TAS: Traceable Author Statement. | |
DownLoad: CSV| Gene | Cytoband | Mean mRNA expression (Altered) | Mean mRNA expression (Unaltered) | Standard deviation of mRNA expression (Altered) | Standard deviation of mRNA expression (Unaltered) | p-Value | q-Value |
| SCARNA2 | 1q13.1 | 3.7 | 2.44 | 0.26 | 1.43 | 5.65E−09 | 8.17E−05 |
| ZFAND1 | 8q21.13 | 3.46 | 4.11 | 0.19 | 0.68 | 6.17E−06 | 0.0446 |
| NGEF | 2q37 | 2.62 | 1.25 | 0.44 | 1.66 | 1.75E−05 | 0.0845 |
| PTAFR | 1p35−p34.3 | 2.13 | 2.54 | 0.15 | 1.05 | 4.18E−05 | 0.151 |
| STK17A | 7p13 | 2.54 | 2.91 | 0.14 | 0.54 | 9.73E−05 | 0.282 |
| CHI3L1 | 1q32.1 | 1.63 | 2.83 | 0.49 | 2.09 | 1.22E−04 | 0.295 |
| CEP120 | 5q23.2 | 1.62 | 2.25 | 0.25 | 0.6 | 2.99E−04 | 0.552 |
| TPD52L1 | 6q22−q23 | 2.38 | 0.92 | 0.64 | 2.11 | 3.48E−04 | 0.552 |
| ZNF232 | 17p13.2 | 0.95 | 1.4 | 0.2 | 0.62 | 3.82E−04 | 0.552 |
| IGSF9 | 1q22−q23 | 2.97 | 1.53 | 0.64 | 1.86 | 4.08E−04 | 0.552 |
| CDH13 | 16q23.3 | 0.98 | 1.93 | 0.42 | 1.06 | 4.66E−04 | 0.552 |
| RMDN1 | 8q21.3 | 3.15 | 3.56 | 0.19 | 0.56 | 5.06E−04 | 0.552 |
| PAPD4 | 5q14.1 | 3.07 | 3.6 | 0.23 | 0.48 | 5.95E−04 | 0.552 |
| GPR35 | 2q37.3 | 4.76 | 4.08 | 0.33 | 1.42 | 6.08E−04 | 0.552 |
| C1ORF54 | 1q21.2 | 2.06 | 3.07 | 0.45 | 0.9 | 6.71E−04 | 0.552 |
| CSNK1G3 | 5q23 | 2.43 | 2.89 | 0.21 | 0.53 | 6.74E−04 | 0.552 |
| FGF11 | 17p13.1 | −1.56 | −0.48 | 0.51 | 1.33 | 7.10E−04 | 0.552 |
| CAMK2N2 | 3q27.1 | −1.45 | −0.32 | 0.55 | 1.84 | 7.19E−04 | 0.552 |
| CSNK1A1 | 5q32 | 4.36 | 4.8 | 0.2 | 0.4 | 7.51E−04 | 0.552 |
| CREBL2 | 12p13 | 3.29 | 3.83 | 0.25 | 0.57 | 7.74E−04 | 0.552 |
| CORO2A | 9q22.3 | 3.66 | 2.87 | 0.38 | 1.21 | 8.06E−04 | 0.552 |
| UGT8 | 4q26 | 3.44 | 2.26 | 0.59 | 2.02 | 8.62E−04 | 0.552 |
| ZSCAN32 | 16p13.3 | 1.29 | 1.88 | 0.27 | 0.44 | 9.04E−04 | 0.552 |
| DNAJC22 | 12q13.12 | 3.23 | 2.4 | 0.42 | 1.71 | 9.16E−04 | 0.552 |
DownLoad: CSV| Official Symbol | Entrez Gene | Pubmed ID |
| PPBP | 5473 | 16169070, 21900206 |
| EEF1G | 1937 | 16169070 |
| KAT5 | 10524 | 16169070 |
| EPHA4 | 2043 | 10366629 |
| EPHA3 | 2042 | 9195962 |
| XRCC6 | 2547 | 21900206 |
DownLoad: CSV| Gene symbol | Full name | Ratio in diffuse-type GC to MSC (GAPDH normalized) | Localization (The human protein atlas, supported) | Localization (UniProt) |
| BMI1 /// COMMD3-BMI1 | BMI1 proto-oncogene, polycomb ring finger /// COMMD3-BMI1 readthrough | 1.76 | Localized to the Nucleus (approved), Nuclear bodies (approved) | Nucleus Cytoplasm |
| CXCR4 | C-X-C motif chemokine receptor 4 | 1901.94 | Not available | Cell membrane; Multi-pass membrane protein; Cell junction; Early endosome; Late endosome; Lysosome |
| EFNA1 | ephrin A1 | 216.27 | Not available | Cell membrane; Lipid-anchor 〉 GPI-anchor; Secreted |
| EFNB2 | ephrin B2 | 2.87 | Localized to the Nucleoplasm (supported) | Membrane |
| EPHA5 | EPH receptor A5 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein; Cell projection 〉 axon; Cell projection 〉 dendrite |
| ERBB2 | erb-b2 receptor tyrosine kinase 2 | 3.04 | Localized to the Plasma membrane (supported) In addition localized to the Cytosol (supported) |
Isoform 1: Cell membrane; Single-pass type I membrane protein; Cytoplasm 〉 perinuclear region; Nucleus; Isoform 2 & 3: Cytoplasm; Nucleus |
| ITGB1 | integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) | 0.31 | Localized to the Plasma membrane (supported), Focal adhesion sites (supported) | Cell membrane; Single-pass type I membrane protein; Cell projection 〉 invadopodium membrane; Single-pass type I membrane protein; Cell projection 〉 ruffle membrane; Single-pass type I membrane protein; Recycling endosome; Melanosome; Cleavage furrow; Cell projection 〉 lamellipodium; Cell projection 〉 ruffle; Cell junction 〉 focal adhesion; Cell surface |
| NANOG | Nanog homeobox | Signal intensity is low | Not available | Nucleus |
| NOTCH1 | notch 1 | 6.94 | Localized to the Nucleoplasm (approved) | Cell membrane; Single-pass type I membrane protein |
| POU5F1 | POU class 5 homeobox 1 | Signal intensity is low | Localized to the Nucleoplasm (supported) In addition localized to the Cytosol (supported) |
Cytoplasm Nucleus |
| RUNX2 | runt related transcription factor 2 | 0.79 | Localized to the Nucleoplasm (validated) | Nucleus |
| SFRP1 | Secreted frizzled-related protein 1 | 5.22 | Nucleoli (approved) | Secreted |
| SHH | sonic hedgehog | Signal intensity is low | Not available | Sonic hedgehog protein C-product: Secreted 〉 extracellular space; Sonic hedgehog protein N-product: Cell membrane; Lipid-anchor |
| SNAI1 | snail family transcriptional repressor 1 | Signal intensity is low | Localized to the Nucleus (supported), Cytosol (supported) | Nucleus Cytoplasm |
| SNAI2 | snail family transcriptional repressor 2 | 0.30 | Localized to the Nucleus (approved) | Nucleus Cytoplasm |
| SOX2 | SRY-box 2 | 47.16 | Localized to the Nucleoplasm (supported) | Nucleus |
| APC | APC, WNT signaling pathway regulator | 1.03 | Not available | Cell junction 〉 adherens junction; Cytoplasm 〉 cytoskeleton; Cell projection 〉 lamellipodium; Cell projection 〉 ruffle membrane; Cytoplasm; Cell membrane |
| CDH1 | cadherin 1 | 228.47 | Localized to the Plasma membrane (supported), Cell Junctions (supported) In addition localized to the Golgi apparatus (supported) |
Cell junction; Cell membrane; Single-pass type I membrane protein; Endosome; Golgi apparatus 〉 trans-Golgi network |
| CDH10 | cadherin 10 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDH12 | cadherin 12 | Signal intensity is low | Localized to the Vesicles (approved) | Cell membrane; Single-pass type I membrane protein |
| CDH18 | cadherin 18 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDH23 | cadherin 23 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDH4 | cadherin 4 | Signal intensity is low | Localized to the Plasma membrane (validated) | Cell membrane; Single-pass type I membrane protein |
| CDH9 | cadherin 9 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDKN2A | cyclin dependent kinase inhibitor 2A | 0.23 | Localized to the Nucleoli (validated) | Cytoplasm Nucleus |
| CELSR1 | cadherin, EGF LAG seven-pass G-type receptor 1 (flamingo homolog, Drosophila) | Signal intensity is low | Localized to the Plasma membrane (supported) | Cell membrane; Multi-pass membrane protein |
| CELSR3 | cadherin EGF LAG seven-pass G-type receptor 3 | Signal intensity is low | Not available | Cell membrane; Multi-pass membrane protein |
| CNTN6 | contactin 6 | Signal intensity is low | Not available | Cell membrane; Lipid-anchor 〉 GPI-anchor |
| COL12A1 | collagen type XII alpha 1 chain | 0.14 | Localized to the Nucleus (approved) | Secreted 〉 extracellular space 〉 extracellular matrix |
| COL14A1 | collagen type XIV alpha 1 chain | 1.59 | Localized to the Vesicles (approved) | Secreted 〉 extracellular space 〉 extracellular matrix |
| COL20A1 | collagen type XX alpha 1 chain | Signal intensity is low | Not available | Secreted 〉 extracellular space |
| CREBBP | CREB binding protein | 1.89 | Localized to the Nucleoplasm (validated) In addition localized to the Nuclear bodies (validated) |
Cytoplasm Nucleus |
| CUX1 | cut-like homeobox 1 | 3.87 | Localized to the Nucleoplasm (supported), Golgi apparatus (supported) | Nucleus |
| DCC | deleted in colorectal carcinoma | Signal intensity is low | Localized to the Golgi apparatus (approved) | Membrane; Single-pass type I membrane protein |
| EGFR | epidermal growth factor receptor | 2.08 | Localized to the Plasma membrane (validated) | Cell membrane; Single-pass type I membrane protein Endoplasmic reticulum membrane; Single-pass type I membrane protein Golgi apparatus membrane; Single-pass type I membrane protein Nucleus membrane; Single-pass type I membrane protein Endosome; Endosome membrane Nucleus |
| ERBB3 | erb-b2 receptor tyrosine kinase 3 | 167.50 | Localized to the Actin filaments (approved) In addition localized to the Plasma membrane (supported) |
Isoform 1: Cell membrane; Single-pass type I membrane protein Isoform 2: Secreted |
| ERBB4 | erb-b2 receptor tyrosine kinase 4 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| FAT1 | FAT atypical cadherin 1 | 0.88 | Not available | Cell membrane; Single-pass type I membrane protein Nucleus Cytoplasm 〉 perinuclear region |
| FAT2 | FAT atypical cadherin 2 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein Cell junction Nucleus |
| FAT3 | FAT atypical cadherin 3 | Signal intensity is low | Not available | Membrane; Single-pass type I membrane protein |
| FBN1 | fibrillin 1 | 0.20 | Localized to the Cytosol (approved) | Secreted |
| FBXW7 | F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase | 2.53 | Localized to the Nucleoplasm (supported) In addition localized to the Vesicles (approved) |
Isoform 1: Nucleus 〉 nucleoplasm Isoform 2: Cytoplasm Isoform 3: Nucleus 〉 nucleolus |
| FLNA | filamin A | 1.45 | Localized to the Plasma membrane (validated), Actin filaments (validated), Cytosol (validated) | Cytoplasm 〉 cell cortex Cytoplasm 〉 cytoskeleton |
| GLI3 | GLI family zinc finger 3 | 1.34 | Not available | Nucleus; Cytoplasm; Cell projection 〉 cilium |
| GRB7 | growth factor receptor-bound protein 7 | Signal intensity is low | Localized to the Plasma membrane (supported) | Cytoplasm; Cell junction 〉 focal adhesion; Cell membrane; Peripheral membrane protein; Cytoplasmic side; Cytoplasmic granule Cell projection |
| HSPG2 | heparan sulfate proteoglycan 2 | 1.29 | Localized to the Nucleoplasm (approved), Plasma membrane (approved), Cytosol (approved) | Secreted 〉 extracellular space 〉 extracellular matrix 〉 basement membrane |
| KRAS | KRAS proto-oncogene, GTPase | 1.75 | Not available | Cell membrane; Lipid-anchor; Cytoplasmic side Cytoplasm 〉 cytosol |
| LRP2 | low density lipoprotein receptor-related protein 2 | Signal intensity is low | Localized to the Vesicles (approved), Mitochondria (approved) | Membrane; Single-pass type I membrane protein Membrane 〉 coated pit |
| MYC | v-myc myelocytomatosis viral oncogene homolog (avian) | 2.85 | Localized to the Nucleoplasm (validated) | Nucleus 〉 nucleoplasm Nucleus 〉 nucleolus |
| NFATC2 | nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 | 27.85 | Localized to the Nucleoplasm (supported), Cytosol (supported) | Cytoplasm Nucleus |
| PCDH10 | protocadherin 10 | 0.07 | Localized to the Golgi apparatus (approved) In addition localized to the Nucleus (approved), Vesicles (approved) |
Cell membrane; Single-pass type I membrane protein |
| PCDH15 | protocadherin-related 15 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein Isoform 3 :Secreted |
| PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | 1.33 | Localized to the Cytosol (approved) | GO - Cellular component cytosol Source: Reactome lamellipodium Source: Ensembl phosphatidylinositol 3-kinase complex Source: BHF-UCL phosphatidylinositol 3-kinase complex, class IA Source: UniProtKB plasma membrane Source: GO_Central |
| PSME4 | proteasome (prosome, macropain) activator subunit 4 | 1.97 | Localized to the Nucleoplasm (supported) | Cytoplasm 〉 cytosol Nucleus Nucleus speckle |
| PTEN | phosphatase and tensin homolog | 15.55 | Localized to the Nucleoplasm (supported) In addition localized to the Cytosol (supported) |
Cytoplasm Nucleus Nucleus 〉 PML body Isoform alpha: Secreted |
| RELN | reelin | Signal intensity is low | Localized to the Focal adhesion sites (approved) In addition localized to the Plasma membrane (approved) |
Secreted 〉 extracellular space 〉 extracellular matrix |
| SALL4 | sal-like 4 (Drosophila) | Signal intensity is low | Localized to the Nucleoplasm (validated) | Cytoplasm Nucleus |
| SMAD4 | SMAD family member 4 | 2.32 | Localized to the Nucleoplasm (supported), Cytosol (supported) In addition localized to the Centrosome (approved) |
Cytoplasm Nucleus |
| SPTA1 | spectrin, alpha, erythrocytic 1 (elliptocytosis 2) | Signal intensity is low | Not available | Cytoplasm 〉 cytoskeleton Cytoplasm 〉 cell cortex |
| TP53 | tumor protein p53 | Signal intensity is low | Localized to the Nucleoplasm (validated) | Cytoplasm Nucleus Nucleus 〉 PML body Endoplasmic reticulum Mitochondrion matrix |
| TRIO | triple functional domain (PTPRF interacting) | 0.92 | Localized to the Cytosol (approved) In addition localized to the Vesicles (approved) |
Cytoplasm |
DownLoad: CSV| GO class (direct) | Evidence |
| anchored component of plasma membrane | IBA |
| angiogenesis | IBA |
| aortic valve morphogenesis | ISS |
| axon guidance | IBA |
| cell migration | IDA |
| cell-cell signaling | TAS |
| endocardial cushion to mesenchymal transition involved in heart valve formation | ISS |
| ephrin receptor binding | IBA, IPI |
| ephrin receptor signaling pathway | IBA, IDA, IGI, TAS |
| extracellular region | IEA |
| integral component of plasma membrane | TAS |
| mitral valve morphogenesis | ISS |
| negative regulation of dendritic spine morphogenesis | ISS |
| negative regulation of epithelial to mesenchymal transition | ISS |
| negative regulation of MAPK cascade | IEA |
| negative regulation of proteolysis involved in cellular protein catabolic process | IGI |
| negative regulation of thymocyte apoptotic process | IEA |
| negative regulation of transcription by RNA polymerase II | ISS |
| notochord formation | IEA |
| plasma membrane | IBA, NAS, TAS |
| positive regulation of amyloid-beta formation | IDA |
| positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process | IGI |
| positive regulation of MAPK cascade | IEA |
| positive regulation of peptidyl-tyrosine phosphorylation | IDA |
| positive regulation of protein phosphorylation | IGI |
| GO class (direct) | Evidence |
| positive regulation of protein tyrosine kinase activity | IGI |
| protein binding | IPI |
| protein stabilization | IGI |
| regulation of angiogenesis | IEA |
| regulation of axonogenesis | IEA |
| regulation of blood vessel endothelial cell migration | IEA |
| regulation of cell adhesion mediated by integrin | IDA |
| regulation of peptidyl-tyrosine phosphorylation | ISS |
| signaling receptor binding | TAS |
| substrate adhesion-dependent cell spreading | IDA |
| IBA: Inferred from Biological Ancestry, IDA: Inferred from Direct Assay, IEA: Inferred from Electronic Annotation, IGI: Inferred from Genetic Interaction, IPI: Inferred from Physical Interaction, ISS: Inferred from Sequence or structural Similarity, NAS: Non-traceable Author Statement, TAS: Traceable Author Statement. | |
| Gene | Cytoband | Mean mRNA expression (Altered) | Mean mRNA expression (Unaltered) | Standard deviation of mRNA expression (Altered) | Standard deviation of mRNA expression (Unaltered) | p-Value | q-Value |
| SCARNA2 | 1q13.1 | 3.7 | 2.44 | 0.26 | 1.43 | 5.65E−09 | 8.17E−05 |
| ZFAND1 | 8q21.13 | 3.46 | 4.11 | 0.19 | 0.68 | 6.17E−06 | 0.0446 |
| NGEF | 2q37 | 2.62 | 1.25 | 0.44 | 1.66 | 1.75E−05 | 0.0845 |
| PTAFR | 1p35−p34.3 | 2.13 | 2.54 | 0.15 | 1.05 | 4.18E−05 | 0.151 |
| STK17A | 7p13 | 2.54 | 2.91 | 0.14 | 0.54 | 9.73E−05 | 0.282 |
| CHI3L1 | 1q32.1 | 1.63 | 2.83 | 0.49 | 2.09 | 1.22E−04 | 0.295 |
| CEP120 | 5q23.2 | 1.62 | 2.25 | 0.25 | 0.6 | 2.99E−04 | 0.552 |
| TPD52L1 | 6q22−q23 | 2.38 | 0.92 | 0.64 | 2.11 | 3.48E−04 | 0.552 |
| ZNF232 | 17p13.2 | 0.95 | 1.4 | 0.2 | 0.62 | 3.82E−04 | 0.552 |
| IGSF9 | 1q22−q23 | 2.97 | 1.53 | 0.64 | 1.86 | 4.08E−04 | 0.552 |
| CDH13 | 16q23.3 | 0.98 | 1.93 | 0.42 | 1.06 | 4.66E−04 | 0.552 |
| RMDN1 | 8q21.3 | 3.15 | 3.56 | 0.19 | 0.56 | 5.06E−04 | 0.552 |
| PAPD4 | 5q14.1 | 3.07 | 3.6 | 0.23 | 0.48 | 5.95E−04 | 0.552 |
| GPR35 | 2q37.3 | 4.76 | 4.08 | 0.33 | 1.42 | 6.08E−04 | 0.552 |
| C1ORF54 | 1q21.2 | 2.06 | 3.07 | 0.45 | 0.9 | 6.71E−04 | 0.552 |
| CSNK1G3 | 5q23 | 2.43 | 2.89 | 0.21 | 0.53 | 6.74E−04 | 0.552 |
| FGF11 | 17p13.1 | −1.56 | −0.48 | 0.51 | 1.33 | 7.10E−04 | 0.552 |
| CAMK2N2 | 3q27.1 | −1.45 | −0.32 | 0.55 | 1.84 | 7.19E−04 | 0.552 |
| CSNK1A1 | 5q32 | 4.36 | 4.8 | 0.2 | 0.4 | 7.51E−04 | 0.552 |
| CREBL2 | 12p13 | 3.29 | 3.83 | 0.25 | 0.57 | 7.74E−04 | 0.552 |
| CORO2A | 9q22.3 | 3.66 | 2.87 | 0.38 | 1.21 | 8.06E−04 | 0.552 |
| UGT8 | 4q26 | 3.44 | 2.26 | 0.59 | 2.02 | 8.62E−04 | 0.552 |
| ZSCAN32 | 16p13.3 | 1.29 | 1.88 | 0.27 | 0.44 | 9.04E−04 | 0.552 |
| DNAJC22 | 12q13.12 | 3.23 | 2.4 | 0.42 | 1.71 | 9.16E−04 | 0.552 |
| Official Symbol | Entrez Gene | Pubmed ID |
| PPBP | 5473 | 16169070, 21900206 |
| EEF1G | 1937 | 16169070 |
| KAT5 | 10524 | 16169070 |
| EPHA4 | 2043 | 10366629 |
| EPHA3 | 2042 | 9195962 |
| XRCC6 | 2547 | 21900206 |
| Gene symbol | Full name | Ratio in diffuse-type GC to MSC (GAPDH normalized) | Localization (The human protein atlas, supported) | Localization (UniProt) |
| BMI1 /// COMMD3-BMI1 | BMI1 proto-oncogene, polycomb ring finger /// COMMD3-BMI1 readthrough | 1.76 | Localized to the Nucleus (approved), Nuclear bodies (approved) | Nucleus Cytoplasm |
| CXCR4 | C-X-C motif chemokine receptor 4 | 1901.94 | Not available | Cell membrane; Multi-pass membrane protein; Cell junction; Early endosome; Late endosome; Lysosome |
| EFNA1 | ephrin A1 | 216.27 | Not available | Cell membrane; Lipid-anchor 〉 GPI-anchor; Secreted |
| EFNB2 | ephrin B2 | 2.87 | Localized to the Nucleoplasm (supported) | Membrane |
| EPHA5 | EPH receptor A5 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein; Cell projection 〉 axon; Cell projection 〉 dendrite |
| ERBB2 | erb-b2 receptor tyrosine kinase 2 | 3.04 | Localized to the Plasma membrane (supported) In addition localized to the Cytosol (supported) |
Isoform 1: Cell membrane; Single-pass type I membrane protein; Cytoplasm 〉 perinuclear region; Nucleus; Isoform 2 & 3: Cytoplasm; Nucleus |
| ITGB1 | integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) | 0.31 | Localized to the Plasma membrane (supported), Focal adhesion sites (supported) | Cell membrane; Single-pass type I membrane protein; Cell projection 〉 invadopodium membrane; Single-pass type I membrane protein; Cell projection 〉 ruffle membrane; Single-pass type I membrane protein; Recycling endosome; Melanosome; Cleavage furrow; Cell projection 〉 lamellipodium; Cell projection 〉 ruffle; Cell junction 〉 focal adhesion; Cell surface |
| NANOG | Nanog homeobox | Signal intensity is low | Not available | Nucleus |
| NOTCH1 | notch 1 | 6.94 | Localized to the Nucleoplasm (approved) | Cell membrane; Single-pass type I membrane protein |
| POU5F1 | POU class 5 homeobox 1 | Signal intensity is low | Localized to the Nucleoplasm (supported) In addition localized to the Cytosol (supported) |
Cytoplasm Nucleus |
| RUNX2 | runt related transcription factor 2 | 0.79 | Localized to the Nucleoplasm (validated) | Nucleus |
| SFRP1 | Secreted frizzled-related protein 1 | 5.22 | Nucleoli (approved) | Secreted |
| SHH | sonic hedgehog | Signal intensity is low | Not available | Sonic hedgehog protein C-product: Secreted 〉 extracellular space; Sonic hedgehog protein N-product: Cell membrane; Lipid-anchor |
| SNAI1 | snail family transcriptional repressor 1 | Signal intensity is low | Localized to the Nucleus (supported), Cytosol (supported) | Nucleus Cytoplasm |
| SNAI2 | snail family transcriptional repressor 2 | 0.30 | Localized to the Nucleus (approved) | Nucleus Cytoplasm |
| SOX2 | SRY-box 2 | 47.16 | Localized to the Nucleoplasm (supported) | Nucleus |
| APC | APC, WNT signaling pathway regulator | 1.03 | Not available | Cell junction 〉 adherens junction; Cytoplasm 〉 cytoskeleton; Cell projection 〉 lamellipodium; Cell projection 〉 ruffle membrane; Cytoplasm; Cell membrane |
| CDH1 | cadherin 1 | 228.47 | Localized to the Plasma membrane (supported), Cell Junctions (supported) In addition localized to the Golgi apparatus (supported) |
Cell junction; Cell membrane; Single-pass type I membrane protein; Endosome; Golgi apparatus 〉 trans-Golgi network |
| CDH10 | cadherin 10 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDH12 | cadherin 12 | Signal intensity is low | Localized to the Vesicles (approved) | Cell membrane; Single-pass type I membrane protein |
| CDH18 | cadherin 18 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDH23 | cadherin 23 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDH4 | cadherin 4 | Signal intensity is low | Localized to the Plasma membrane (validated) | Cell membrane; Single-pass type I membrane protein |
| CDH9 | cadherin 9 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| CDKN2A | cyclin dependent kinase inhibitor 2A | 0.23 | Localized to the Nucleoli (validated) | Cytoplasm Nucleus |
| CELSR1 | cadherin, EGF LAG seven-pass G-type receptor 1 (flamingo homolog, Drosophila) | Signal intensity is low | Localized to the Plasma membrane (supported) | Cell membrane; Multi-pass membrane protein |
| CELSR3 | cadherin EGF LAG seven-pass G-type receptor 3 | Signal intensity is low | Not available | Cell membrane; Multi-pass membrane protein |
| CNTN6 | contactin 6 | Signal intensity is low | Not available | Cell membrane; Lipid-anchor 〉 GPI-anchor |
| COL12A1 | collagen type XII alpha 1 chain | 0.14 | Localized to the Nucleus (approved) | Secreted 〉 extracellular space 〉 extracellular matrix |
| COL14A1 | collagen type XIV alpha 1 chain | 1.59 | Localized to the Vesicles (approved) | Secreted 〉 extracellular space 〉 extracellular matrix |
| COL20A1 | collagen type XX alpha 1 chain | Signal intensity is low | Not available | Secreted 〉 extracellular space |
| CREBBP | CREB binding protein | 1.89 | Localized to the Nucleoplasm (validated) In addition localized to the Nuclear bodies (validated) |
Cytoplasm Nucleus |
| CUX1 | cut-like homeobox 1 | 3.87 | Localized to the Nucleoplasm (supported), Golgi apparatus (supported) | Nucleus |
| DCC | deleted in colorectal carcinoma | Signal intensity is low | Localized to the Golgi apparatus (approved) | Membrane; Single-pass type I membrane protein |
| EGFR | epidermal growth factor receptor | 2.08 | Localized to the Plasma membrane (validated) | Cell membrane; Single-pass type I membrane protein Endoplasmic reticulum membrane; Single-pass type I membrane protein Golgi apparatus membrane; Single-pass type I membrane protein Nucleus membrane; Single-pass type I membrane protein Endosome; Endosome membrane Nucleus |
| ERBB3 | erb-b2 receptor tyrosine kinase 3 | 167.50 | Localized to the Actin filaments (approved) In addition localized to the Plasma membrane (supported) |
Isoform 1: Cell membrane; Single-pass type I membrane protein Isoform 2: Secreted |
| ERBB4 | erb-b2 receptor tyrosine kinase 4 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein |
| FAT1 | FAT atypical cadherin 1 | 0.88 | Not available | Cell membrane; Single-pass type I membrane protein Nucleus Cytoplasm 〉 perinuclear region |
| FAT2 | FAT atypical cadherin 2 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein Cell junction Nucleus |
| FAT3 | FAT atypical cadherin 3 | Signal intensity is low | Not available | Membrane; Single-pass type I membrane protein |
| FBN1 | fibrillin 1 | 0.20 | Localized to the Cytosol (approved) | Secreted |
| FBXW7 | F-box and WD repeat domain containing 7, E3 ubiquitin protein ligase | 2.53 | Localized to the Nucleoplasm (supported) In addition localized to the Vesicles (approved) |
Isoform 1: Nucleus 〉 nucleoplasm Isoform 2: Cytoplasm Isoform 3: Nucleus 〉 nucleolus |
| FLNA | filamin A | 1.45 | Localized to the Plasma membrane (validated), Actin filaments (validated), Cytosol (validated) | Cytoplasm 〉 cell cortex Cytoplasm 〉 cytoskeleton |
| GLI3 | GLI family zinc finger 3 | 1.34 | Not available | Nucleus; Cytoplasm; Cell projection 〉 cilium |
| GRB7 | growth factor receptor-bound protein 7 | Signal intensity is low | Localized to the Plasma membrane (supported) | Cytoplasm; Cell junction 〉 focal adhesion; Cell membrane; Peripheral membrane protein; Cytoplasmic side; Cytoplasmic granule Cell projection |
| HSPG2 | heparan sulfate proteoglycan 2 | 1.29 | Localized to the Nucleoplasm (approved), Plasma membrane (approved), Cytosol (approved) | Secreted 〉 extracellular space 〉 extracellular matrix 〉 basement membrane |
| KRAS | KRAS proto-oncogene, GTPase | 1.75 | Not available | Cell membrane; Lipid-anchor; Cytoplasmic side Cytoplasm 〉 cytosol |
| LRP2 | low density lipoprotein receptor-related protein 2 | Signal intensity is low | Localized to the Vesicles (approved), Mitochondria (approved) | Membrane; Single-pass type I membrane protein Membrane 〉 coated pit |
| MYC | v-myc myelocytomatosis viral oncogene homolog (avian) | 2.85 | Localized to the Nucleoplasm (validated) | Nucleus 〉 nucleoplasm Nucleus 〉 nucleolus |
| NFATC2 | nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2 | 27.85 | Localized to the Nucleoplasm (supported), Cytosol (supported) | Cytoplasm Nucleus |
| PCDH10 | protocadherin 10 | 0.07 | Localized to the Golgi apparatus (approved) In addition localized to the Nucleus (approved), Vesicles (approved) |
Cell membrane; Single-pass type I membrane protein |
| PCDH15 | protocadherin-related 15 | Signal intensity is low | Not available | Cell membrane; Single-pass type I membrane protein Isoform 3 :Secreted |
| PIK3CA | phosphoinositide-3-kinase, catalytic, alpha polypeptide | 1.33 | Localized to the Cytosol (approved) | GO - Cellular component cytosol Source: Reactome lamellipodium Source: Ensembl phosphatidylinositol 3-kinase complex Source: BHF-UCL phosphatidylinositol 3-kinase complex, class IA Source: UniProtKB plasma membrane Source: GO_Central |
| PSME4 | proteasome (prosome, macropain) activator subunit 4 | 1.97 | Localized to the Nucleoplasm (supported) | Cytoplasm 〉 cytosol Nucleus Nucleus speckle |
| PTEN | phosphatase and tensin homolog | 15.55 | Localized to the Nucleoplasm (supported) In addition localized to the Cytosol (supported) |
Cytoplasm Nucleus Nucleus 〉 PML body Isoform alpha: Secreted |
| RELN | reelin | Signal intensity is low | Localized to the Focal adhesion sites (approved) In addition localized to the Plasma membrane (approved) |
Secreted 〉 extracellular space 〉 extracellular matrix |
| SALL4 | sal-like 4 (Drosophila) | Signal intensity is low | Localized to the Nucleoplasm (validated) | Cytoplasm Nucleus |
| SMAD4 | SMAD family member 4 | 2.32 | Localized to the Nucleoplasm (supported), Cytosol (supported) In addition localized to the Centrosome (approved) |
Cytoplasm Nucleus |
| SPTA1 | spectrin, alpha, erythrocytic 1 (elliptocytosis 2) | Signal intensity is low | Not available | Cytoplasm 〉 cytoskeleton Cytoplasm 〉 cell cortex |
| TP53 | tumor protein p53 | Signal intensity is low | Localized to the Nucleoplasm (validated) | Cytoplasm Nucleus Nucleus 〉 PML body Endoplasmic reticulum Mitochondrion matrix |
| TRIO | triple functional domain (PTPRF interacting) | 0.92 | Localized to the Cytosol (approved) In addition localized to the Vesicles (approved) |
Cytoplasm |
