EPHA3

Gene Summary

Gene:EPHA3; EPH receptor A3
Aliases: EK4, ETK, HEK, ETK1, HEK4, TYRO4
Location:3p11.1
Summary:This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. This gene encodes a protein that binds ephrin-A ligands. Two alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:ephrin type-A receptor 3
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Disease Progression
  • Melanoma
  • Reproducibility of Results
  • Single Nucleotide Polymorphism
  • Young Adult
  • Base Sequence
  • Chromosome 3
  • Prostate Cancer
  • Cell Proliferation
  • Neoplastic Cell Transformation
  • Mutation
  • Messenger RNA
  • Tumor Suppressor Proteins
  • EPHA3
  • Biomarkers, Tumor
  • Cancer Gene Expression Regulation
  • Gene Expression Profiling
  • Colorectal Cancer
  • DNA Methylation
  • Small Cell Lung Cancer
  • Polymerase Chain Reaction
  • Immunohistochemistry
  • Case-Control Studies
  • Ubiquitin-Protein Ligases
  • Genetic Predisposition
  • Lung Cancer
  • Receptor Protein-Tyrosine Kinases
  • Androgen Receptors
  • DNA Mutational Analysis
  • Tumor Suppressor Gene
  • Apoptosis
  • Cell Movement
  • Oligonucleotide Array Sequence Analysis
  • Neoplasm Metastasis
  • Western Blotting
  • beta-Galactosidase
  • Germ-Line Mutation
  • VEGFA
  • Skin Cancer
  • Protein-Tyrosine Kinases
Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: EPHA3 (cancer-related)

Chen X, Lu B, Ma Q, et al.
EphA3 inhibits migration and invasion of esophageal cancer cells by activating the mesenchymal‑epithelial transition process.
Int J Oncol. 2019; 54(2):722-732 [PubMed] Related Publications
Eph receptor tyrosine kinases are critical for cell‑cell communication during normal and oncogenic development. Eph receptor A3 (EphA3) expression is associated with tumor promotion in certain types of cancer; however, it acts as a tumor suppressor in others. The expression levels of EphA3 and its effects on tumor progression in esophageal squamous cell carcinoma (ESCC) cell lines were determined using reverse transcription‑quantitative polymerase chain reaction analysis and a Transwell invasion assay. The present study demonstrated that EphA3 expression was decreased in ESCC tissues and cell lines. Treatment with the DNA methylation inhibitor 5‑aza‑2'‑deoxycytidine increased the mRNA expression levels of EphA3 in the ESCC cell lines KYSE510 and KYSE30. In addition, overexpression of EphA3 in KYSE450 and KYSE510 cells inhibited cell migration and invasion. EphA3 overexpression also decreased RhoA GTPase. Furthermore, EphA3 overexpression induced mesenchymal‑epithelial transition, as demonstrated by epithelial‑like morphological alterations, increased expression of epithelial proteins (E‑cadherin and the tight junction protein 1 zonula occludens‑1) and decreased expression of mesenchymal proteins (Vimentin, N‑cadherin and Snail). Conversely, silencing EphA3 in KYSE410 cells triggered epithelial‑mesenchymal transition, and promoted cell migration and invasion. These results suggested that EphA3 may serve a tumor‑suppressor role in ESCC.

Sharma P, Debinski W
Receptor-Targeted Glial Brain Tumor Therapies.
Int J Mol Sci. 2018; 19(11) [PubMed] Free Access to Full Article Related Publications
Among primary brain tumors, malignant gliomas are notably difficult to manage. The higher-grade tumors represent an unmet need in medicine. There have been extensive efforts to implement receptor-targeted therapeutic approaches directed against gliomas. These approaches include immunotherapies, such as vaccines, adoptive immunotherapy, and passive immunotherapy. Targeted cytotoxic radio energy and pro-drug activation have been designed specifically for brain tumors. The field of targeting through receptors progressed significantly with the discovery of an interleukin 13 receptor alpha 2 (IL-13RA2) as a tumor-associated receptor over-expressed in most patients with glioblastoma (GBM) but not in normal brain. IL-13RA2 has been exploited in novel experimental therapies with very encouraging clinical responses. Other receptors are specifically over-expressed in many patients with GBM, such as EphA2 and EphA3 receptors, among others. These findings are important in view of the heterogeneity of GBM tumors and multiple tumor compartments responsible for tumor progression and resistance to therapies. The combined targeting of multiple receptors in different tumor compartments should be a preferred way to design novel receptor-targeted therapeutic approaches in gliomas.

Chu L, Wang A, Ni L, et al.
Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting.
Drug Deliv. 2018; 25(1):1634-1641 [PubMed] Free Access to Full Article Related Publications
Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.

Lv XY, Wang J, Huang F, et al.
EphA3 contributes to tumor growth and angiogenesis in human gastric cancer cells.
Oncol Rep. 2018; 40(4):2408-2416 [PubMed] Related Publications
Eph receptor tyrosine kinases and their ephrin ligands, mediate an important cell communication system both in normal and oncogenic development, and play central roles in a series of processes including angiogenesis, stem cell maintenance and cancer metastasis. Eph receptor A3 (EphA3), commonly overexpressed in a broad range of cancers, including gastric cancer (GC), is related to tumor progression. Our previous study revealed that EphA3 may play important roles in tumorigenesis and angiogenesis in GC. However, its exact role and the mechanisms underlying its function in GC remain unclear. In the present study, lentivirus‑mediated RNA interference was employed to knock down the expression of EphA3 in GC HGC‑27 cells. Functional analyses indicated that depletion of EphA3 expression inhibited the cell growth and tumorigenicity of HGC‑27 cells in vitro and in vivo. Furthermore, knockdown of the expression of EphA3 in HGC‑27 cells inhibited tube formation and migration of HUVEC endothelial cells. Tumor angiogenesis in vivo was also inhibited upon EphA3 knockdown in HGC‑27 cells, with reduced microvessel density (MVD) in xenograft models. We further revealed that EphA3 depletion inhibited tumor angiogenesis and migration through the signal transducer and activator of transcription 3/vascular endothelial growth factor (STAT3/VEGF) signaling pathway. These results indicated that EphA3 may be an effective prognostic indicator and a potential target for GC therapy.

Diao X, Chen X, Pi Y, et al.
Androgen receptor induces EPHA3 expression by interacting with transcription factor SP1.
Oncol Rep. 2018; 40(2):1174-1184 [PubMed] Related Publications
Erythropoietin‑producing hepatocellular carcinoma cell surface type‑A receptor 3 (EPHA3) has been found to promote the proliferation and survival of prostate cancer (PCa) cell lines and prostate tumor development in nude mice. However, the regulation of EPHA3 in PCa remains largely unknown. This study is aimed to investigate the association between EPHA3 expression and androgen receptor (AR) signaling and the potential mechanism. We determined mRNA and protein levels of EPHA3 and AR signaling‑related genes in the PCa cell line 22Rv1 by reverse transcription‑polymerase chain reaction (RT‑PCR) and western blotting, respectively. The EPHA3 mRNA and protein levels were both found to be elevated by dihydrotestosterone (DHT) hormone in a dose‑ and time‑dependent manner, as AR and prostate‑specific antigen (PSA) expression were increased. Similarly, EPHA3 protein levels were also increased in the PCa cell line LNCaP stimulated with DHT or mibolerone (Mib). Overexpression of pEGFP‑AR in 22Rv1 cells significantly increased the EphA3 level, while AR knockdown with small interfering RNA (siRNA) for AR (siAR) markedly decreased the expression of EPHA3. The key EPHA3 promoter region associated with AR regulation was evaluated by co‑transfection of various pGL3‑basic‑luciferase reporter plasmids, containing EPHA3 core promoter fragments differing in length, with the AR plasmid or siAR into 22Rv1 cells. AR overexpression in 22Rvl cells raised the EphA3 promoter transcription activity of pGL3‑EPHA3‑Luc (EPHA3‑Luc)‑789, and vice versa. Similarly, luciferase activity of EPHA3‑Luc‑317 was also clearly affected. However, truncated EPHA3‑Luc‑237 without the transcription factor specific protein 1 (SP1) binding sites or EPHA3‑Luc‑789ΔSP1 with modified SP1 binding sites clearly decreased EPHA3 promoter activity regardless of whether AR was overexpressed or blocked. Treatment of 22Rv1 cells with 10 and 100 nM of the SP1 inhibitor mithramycin A for 24 and 48 h significantly reduced EPHA3 mRNA and protein levels. Additionally, selective inhibition of SP1 with siRNA SP1 (siSP1) at various concentration from 25 to 75 nM, reduced the EPHA3 protein level in PCa LNCaP cells, accordingly. Co‑immunoprecipitation (co‑IP) and chromatin IP (ChIP) assays were performed to determine whether AR forms a transcription factor complex with Sp1 that binds the EPHA3 core promoter region to sense androgen induction. The result suggests that the interaction of AR and SP1 contributes to regulate EPHA3 expression, and the SP1 binding sites (‑295~‑261) in the EPHA3 core promoter region is crucial to the regulation of EPHA3 expression in response to androgen hormone stimuli.

Inokuchi M, Nakagawa M, Baogok N, et al.
Prognostic Significance of High EphA1-4 Expression Levels in Locally Advanced Gastric Cancer.
Anticancer Res. 2018; 38(3):1685-1693 [PubMed] Related Publications
BACKGROUND/AIM: Erythropoietin-producing hepatocellular carcinoma receptor A (EphA) is associated with angiogenesis and invasive tumor progression. In this study, we evaluated the EphA1-4 expression levels in advanced gastric cancer.
PATIENTS AND METHODS: Tumor tissues obtained from 114 patients with advanced gastric adenocarcinoma who underwent gastrectomy were analyzed. In addition, the impact of EPHA 1-4 mRNA expression on survival was analyzed using the Kaplan-Meier plotter database on the website.
RESULTS: High EphA 1, 2, and 4 expression levels were significantly related to recurrence (p<0.01, p=0.04, and p<0.01). Both high EphA 1 and 4 expression levels were independent predictors of relapse-free interval (hazard ratio [HR]=2.0, p=0.03; HR=2.4, p=0.03) and disease-specific survival (HR=2.0, 95% p=0.03; HR=2.5, p=0.02) on multivariate analysis. In the Kaplan-Meier plotter database, high EPHA2 mRNA expression was significantly associated with poor survival in patients with gastric cancer (p=0.0098), and high expression levels of EPHA1 and 4 tended to be associated with poor survival (p=0.050, p=0.052).
CONCLUSION: EphA 1, 2, and 4 may play key roles in recurrence and survival in patients with advanced gastric cancer.

Pharo HD, Andresen K, Berg KCG, et al.
A robust internal control for high-precision DNA methylation analyses by droplet digital PCR.
Clin Epigenetics. 2018; 10:24 [PubMed] Free Access to Full Article Related Publications
Background: Droplet digital PCR (ddPCR) allows absolute quantification of nucleic acids and has potential for improved non-invasive detection of DNA methylation. For increased precision of the methylation analysis, we aimed to develop a robust internal control for use in methylation-specific ddPCR.
Methods: Two control design approaches were tested: (a) targeting a genomic region shared across members of a gene family and (b) combining multiple assays targeting different pericentromeric loci on different chromosomes. Through analyses of 34 colorectal cancer cell lines, the performance of the control assay candidates was optimized and evaluated, both individually and in various combinations, using the QX200™ droplet digital PCR platform (Bio-Rad). The best-performing control was tested in combination with assays targeting methylated
Results: A 4Plex panel consisting of
Conclusion: Implementation of a robust internal control, i.e., the 4Plex, and an algorithm for automated threshold determination, PoDCall, in methylation-specific ddPCR increase the precision of DNA methylation analysis.

Mao Y, Pei N, Chen X, et al.
Angiotensin 1-7 Overexpression Mediated by a Capsid-optimized AAV8 Vector Leads to Significant Growth Inhibition of Hepatocellular Carcinoma
Int J Biol Sci. 2018; 14(1):57-68 [PubMed] Free Access to Full Article Related Publications

Zeng Y, Xu Y, Shu R, et al.
Altered expression profiles of circular RNA in colorectal cancer tissues from patients with lung metastasis.
Int J Mol Med. 2017; 40(6):1818-1828 [PubMed] Free Access to Full Article Related Publications
The lung is the most common extra-abdominal site of metastasis in colorectal cancer (CRC), in which circular RNA (circRNA) may have a crucial role. Therefore, the present study detected circRNA expression to identify novel targets to further study lung metastasis in CRC. In the present study, total RNA was extracted from CRC tissues of patients with and without lung metastasis to perform high-throughput microarray assay in order to detect differentially expressed circRNA. Following this, gene ontology (GO) and pathway analyses of the genes producing differentially expressed circRNA were performed to predict the function of circRNA using standard enrichment computational methods. Additionally, the circRNA/microRNA (miRNA) interactions were constructed with bioinformatics methods to predict the binding of miRNA with circRNA. In the CRC tissues from patients with lung metastasis, 431 circRNA were detected to be differentially expressed, including 192 upregulated and 239 downregulated over 2-fold compared with the CRC tissues without metastasis. Furthermore, GO analysis revealed that the genes producing upregulated circRNA were involved in DNA repair, while the genes producing downregulated circRNA were enriched in signal transduction. By pathway analysis, it was identified that the genes producing downregulated circRNA were involved in the nuclear factor-κB and Wnt signaling pathway in the CRC tissues from patients with lung metastasis compared with the CRC tissues without metastasis. In addition, it was demonstrated that hsa_circRNA_105055, hsa_circRNA_086376 and hsa_circRNA_102761 could commonly bind with miR-7 regulating target genes PRKCB, EPHA3, BRCA1 and ABCC1. The findings of the present study may provide a novel perspective on circRNA and lay a foundation for future research of potential roles of circRNA in CRC with lung metastasis.

Heitzer E, Sunitsch S, Gilg MM, et al.
Expanded molecular profiling of myxofibrosarcoma reveals potentially actionable targets.
Mod Pathol. 2017; 30(12):1698-1709 [PubMed] Related Publications
Myxofibrosarcomas are morphologically heterogeneous soft tissue sarcomas lacking a specific immunohistochemical expression profile and recurrent genetic changes. The study was designed to gain further insights into the molecular landscape of myxofibrosarcomas by targeted re-sequencing of known cancer driver hotspot mutations and the analysis of genomewide somatic copy number alterations. A well-defined group of myxofibrosarcomas, including myxofibrosarcomas G1 (n=6), myxofibrosarcomas G3 (n=7), myxofibrosarcomas with morphologically heterogeneous and independently selectable G1 and G3 areas within a tumor (n=8), and myxofibrosarcomas G3 with subsequent tumor recurrence (n=1) or metastatic disease (n=3) were evaluated. Mutational analysis demonstrated mutations in TP53, PTEN, FGFR3, CDKN2A, and RB1. TP53 mutations were seen in 11 (44%) of patients and detected in myxofibrosarcomas G1, G3, with heterogeneous morphology and G3 with subsequent metastases in 1 patient (16%), 3 patients (42%), 2 patients (62.5%), and 3 patients (75%), respectively. Additional mutations were detected in 2 patients, intratumoral mutational heterogeneity in 1 patient. We observed a variety of copy number alterations typical for myxofibrosarcomas, with higher numbers in G3 compared with G1 myxofibrosarcomas. Cluster analysis revealed distinctive features especially in metastatic and recurrent disease. Focal alterations affected CDKN2A, CCND1, CCNE1, EGFR, EPHA3, EPHB1, FGFR1, JUN, NF1, RB1, RET, TP53, and additional novel amplifications in CCNE1, KIT, EGFR, RET, BRAF, NTRK2 were seen in G3 compared with the G1 tumor areas. The total number of focal events in G1 versus G3 tumors differed significantly (P=0.0014). TRIO and RICTOR co-amplification was seen in 8 (44%) G3 and 1 (10%) G1 myxofibrosarcomas and RICTOR amplification alone in 4 (40%) G1 myxofibrosarcomas. TRIO amplification was significantly (P=0.0218) higher in G3 myxofibrosarcomas indicating a late genetic event. These findings support the use of expanded molecular profiling in myxofibrosarcomas to detect drug-able targets to allow patients to participate in basket trials.

Kousa YA, Roushangar R, Patel N, et al.
IRF6 and SPRY4 Signaling Interact in Periderm Development.
J Dent Res. 2017; 96(11):1306-1313 [PubMed] Free Access to Full Article Related Publications
Rare mutations in IRF6 and GRHL3 cause Van der Woude syndrome, an autosomal dominant orofacial clefting disorder. Common variants in IRF6 and GRHL3 also contribute risk for isolated orofacial clefting. Similarly, variants within genes that encode receptor tyrosine kinase (RTK) signaling components, including members of the FGF pathway, EPHA3 and SPRY2, also contribute risk for isolated orofacial clefting. In the mouse, loss of Irf6 or perturbation of Fgf signaling leads to abnormal oral epithelial adhesions and cleft palate. Oral adhesions can result from a disruption of periderm formation. Here, we find that IRF6 and SPRY4 signaling interact in periderm function. We crossed Irf6 heterozygous ( Irf6

La Rocca F, Airoldi I, Di Carlo E, et al.
EphA3 targeting reduces in vitro adhesion and invasion and in vivo growth and angiogenesis of multiple myeloma cells.
Cell Oncol (Dordr). 2017; 40(5):483-496 [PubMed] Related Publications
PURPOSE: Multiple myeloma (MM) is a hematologic malignancy characterized by a clonal expansion of plasma cells (PCs) in the bone marrow (BM). Since MM has so far remained incurable, further insights into its pathogenesis and the concomitant identification of new therapeutic targets are urgently needed. The tyrosine kinase receptor EphA3 is known to be involved in various cellular processes including cell viability, cell movement and cell-cell interactions. Recently, EphA3 has emerged as a potential therapeutic target in several hematologic and solid tumors. Here, we aimed to uncover the role of EphA3 in MM.
METHODS: EphA3 mRNA and protein expression in primary MM bone marrow plasma cells (BMPCs), in MM-derived cell lines and in healthy controls (HCs) was assessed using qRT-PCR, Western blotting and flow cytometry. The effects of siRNA-mediated EphA3 silencing and anti EphA3 antibody (EphA3mAb) treatment on MM PC trafficking and viability were evaluated using in vitro assays. The effects of EphA3mAb treatment were also assessed in two MM-derived mouse xenograft models.
RESULTS: We found that EphA3 was overexpressed in primary MM BMPCs and MM-derived cell lines compared to HCs. We also found that siRNA-mediated EphA3 silencing and EphA3mAb treatment significantly inhibited the ability of MM PCs to adhere to fibronectin and stromal cells and to invade in vitro, without affecting cell proliferation and viability. Gene expression profiling showed that EphA3 silencing resulted in expression modulation of several molecules that regulate adhesion, migration and invasion processes. Importantly, we found that EphA3mAb treatment significantly inhibited in vivo tumor growth and angiogenesis in two MM-derived mouse xenograft models.
CONCLUSIONS: Our findings suggest that EphA3 plays an important role in the pathogenesis of MM and provide support for the notion that its targeting may represent a novel therapeutic opportunity for MM.

Wang W, Jia WD, Hu B, Pan YY
RAB10 overexpression promotes tumor growth and indicates poor prognosis of hepatocellular carcinoma.
Oncotarget. 2017; 8(16):26434-26447 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC), one of the most common and lethal cancers worldwide, has a high recurrence rate with current treatment modalities. Identifying biomarkers for early diagnosis and discovering new sufficient molecular targets for the development of targeted therapies are urgently needed. RAB10, a member of the RAS family, has been shown to be highly expressed in HCC. However, the function of RAB10 in HCC is less studied. Here we report that RAB10 acts as an oncogene in HCC. The shRNA-mediated knockdown of RAB10 significantly reduced the proliferation of HCC cells and colony formation, induced cell cycle arrest at G0/G1 phase and increased apoptosis in vitro. In addition, RAB10 knockdown suppressed HCC growth in nude mice. Moreover, RAB10 silencing decreased the phosphorylation of InsR, Met/HGFR, Ron/MST1R, Ret, c-Kit/SCFR, EphA3, EphB4, Tyro3/Dtk, Axl, Tie2/TEK, VEGFR2/KDR, Akt/PKB/Rac, S6 Ribosomal Protein and c-Abl, while the phosphorylation of HSP27, p38 MAPK, Chk2 and TAK1 increased significantly. These results suggest that RAB10 regulates cell survival and proliferation through multiple oncogenic, cell stress and apoptosis pathways. More importantly, high RAB10 expression levels in HCC cells correlated with a poor prognosis in HCC patients. Therefore, our findings revealed an oncogenic role for RAB10 in the pathogenesis of HCC and that RAB10 is a potential molecular target or a biomarker for HCC.

Caivano A, La Rocca F, Laurenzana I, et al.
Epha3 acts as proangiogenic factor in multiple myeloma.
Oncotarget. 2017; 8(21):34298-34309 [PubMed] Free Access to Full Article Related Publications
This study investigates the role of ephrin receptor A3 (EphA3) in the angiogenesis of Multiple Myeloma (MM) and the effects of a selective target of EphA3 by a specific monoclonal antibody on primary bone marrow endothelial cells (ECs) of MM patients.EphA3 mRNA and protein were evaluated in ECs of MM patients (MMECs), in ECs of patients with monoclonal gammopathies of undetermined significance (MGECs) and in ECs of healthy subjects (control ECs). The effects of EphA3 targeting by mRNA silencing (siRNA) or by the anti EphA3 antibody on the angiogenesis were evaluated. We found that EphA3 is highly expressed in MMECs compared to the other EC types. Loss of function of EphA3 by siRNA significantly inhibited the ability of MMECs to adhere to fibronectin, to migrate and to form tube like structures in vitro, without affecting cell proliferation or viability. In addition, gene expression profiling showed that knockdown of EphA3 down modulated some molecules that regulate adhesion, migration and invasion processes. Interestingly, EphA3 targeting by an anti EphA3 antibody reduced all the MMEC angiogenesis-related functions in vitro. In conclusion, our findings suggest that EphA3 plays an important role in MM angiogenesis.

Klejewski A, Świerczewska M, Zaorska K, et al.
New and Old Genes Associated with Topotecan Resistance Development in Ovarian Cancer Cell Lines.
Anticancer Res. 2017; 37(4):1625-1636 [PubMed] Related Publications
BACKGROUND: Low effectiveness of chemotherapy in ovarian cancer results from development of drug resistance. Topotecan is a drug used as second-line chemotherapy for this cancer type. We analyzed development of topotecan resistance in ovarian cancer cell lines.
MATERIALS AND METHODS: A chemosensitivity assay, MTT test, was performed to assess drug resistance. Quantitative polymerase chain reaction (Q-PCR) assays were performed to determine ABCB1, ABCG2, ALDH1A1, IFIH1, SAMD4 and EPHA3 gene expression.
RESULTS: We observed dose-dependent responses to topotecan. In all topotecan-resistant cell lines an overexpression of ABCG2, IFIH1 and SAMD4 genes was observed. Expression of ABCB1 gene was observed in one cell line. Expression of ALDH1A1 was up-regulated in A2780 and down-regulated in SKOV-3-resistant cell lines. Short-time exposure led to similar patterns of gene expression for the investigated genes.
CONCLUSION: Expression of ABCG2 and ABCB1 genes plays the most important role in topotecan resistance. The role of other investigated genes seems to be complementary.

Andretta E, Cartón-García F, Martínez-Barriocanal Á, et al.
Investigation of the role of tyrosine kinase receptor EPHA3 in colorectal cancer.
Sci Rep. 2017; 7:41576 [PubMed] Free Access to Full Article Related Publications
EPH signaling deregulation has been shown to be important for colorectal carcinogenesis and genome-wide sequencing efforts have identified EPHA3 as one of the most frequently mutated genes in these tumors. However, the role of EPHA3 in colorectal cancer has not been thoroughly investigated. We show here that ectopic expression of wild type EPHA3 in colon cancer cells did not affect their growth, motility/invasion or metastatic potential in vivo. Moreover, overexpression of mutant EPHA3 or deletion of the endogenous mutant EPHA3 in colon cancer cells did not affect their growth or motility. EPHA3 inactivation in mice did not initiate the tumorigenic process in their intestine, and had no effects on tumor size/multiplicity after tumor initiation either genetically or pharmacologically. In addition, immunohistochemical analysis of EPHA3 tumor levels did not reveal associations with survival or clinicopathological features of colorectal cancer patients. In conclusion, we show that EPHA3 does not play a major role in colorectal tumorigenesis. These results significantly contribute to our understanding of the role of EPH signaling during colorectal carcinogenesis, and highlighting the need for detailed functional studies to confirm the relevance of putative cancer driver genes identified in sequencing efforts of the cancer genome.

Hughes A, Clarson J, Gargett T, et al.
Comment on "KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study".
Leuk Res. 2017; 55:55-57 [PubMed] Related Publications

Berzaghi R, Maia VS, Pereira FV, et al.
SOCS1 favors the epithelial-mesenchymal transition in melanoma, promotes tumor progression and prevents antitumor immunity by PD-L1 expression.
Sci Rep. 2017; 7:40585 [PubMed] Free Access to Full Article Related Publications
Silencing of SOCS1 protein with shRNAi lentivirus (shR-SOCS1) led to partial reversion of the tumorigenic phenotype of B16F10-Nex2 melanoma cells. SOCS1 silencing inhibited cell migration and invasion as well as in vitro growth by cell cycle arrest at S phase with increased cell size and nuclei. Down-regulation of SOCS1 decreased the expression of epidermal growth factor receptor, Ins-Rα, and fibroblast growth factor receptors. The present work aimed at analyzing the SOCS1 cell signaling and expression of proteins relevant to tumor development. An RNA microarray analysis of B16F10-Nex2 melanoma cells with SOCS1 silenced by shRNAi-SOCS1 was undertaken in comparison with cells transduced with the empty vector. Among 609 differentially expressed genes, c-Kit, Met and EphA3 cytokine/tyrosine-kinase (TK) receptors were down regulated. A significant decrease in the expression of TK receptors, the phosphorylation of mediators of ERK1/2 and p38 pathways and STAT3 (S727) were observed. Subcutaneous immunization with shR-SOCS1-transduced viable tumor cells rendered protection against melanoma in a syngeneic model, with decreased expression of PD-L1 and of matrix metallo-proteinases (MMPs) and CD-10 in those cells. The present work shows the role of SOCS1 in murine melanoma development and the potential of SOCS1-silenced tumor cells in raising an effective anti-melanoma immune response.

Hu DG, McKinnon RA, Hulin JA, et al.
Novel Nine-Exon AR Transcripts (Exon 1/Exon 1b/Exons 2-8) in Normal and Cancerous Breast and Prostate Cells.
Int J Mol Sci. 2016; 18(1) [PubMed] Free Access to Full Article Related Publications
Nearly 20 different transcripts of the human androgen receptor (AR) are reported with two currently listed as Refseq isoforms in the NCBI database. Isoform 1 encodes wild-type AR (type 1 AR) and isoform 2 encodes the variant AR45 (type 2 AR). Both variants contain eight exons: they share common exons 2-8 but differ in exon 1 with the canonical exon 1 in isoform 1 and the variant exon 1b in isoform 2. Splicing of exon 1 or exon 1b is reported to be mutually exclusive. In this study, we identified a novel exon 1b (1b/TAG) that contains an additional TAG trinucleotide upstream of exon 1b. Moreover, we identified AR transcripts in both normal and cancerous breast and prostate cells that contained either exon 1b or 1b/TAG spliced between the canonical exon 1 and exon 2, generating nine-exon AR transcripts that we have named isoforms 3a and 3b. The proteins encoded by these new AR variants could regulate androgen-responsive reporters in breast and prostate cancer cells under androgen-depleted conditions. Analysis of type 3 AR-GFP fusion proteins showed partial nuclear localization in PC3 cells under androgen-depleted conditions, supporting androgen-independent activation of the AR. Type 3 AR proteins inhibited androgen-induced growth of LNCaP cells. Microarray analysis identified a small set of type 3a AR target genes in LNCaP cells, including genes known to modulate growth and proliferation of prostate cancer (

Charmsaz S, Al-Ejeh F, Yeadon TM, et al.
EphA3 as a target for antibody immunotherapy in acute lymphoblastic leukemia.
Leukemia. 2017; 31(8):1779-1787 [PubMed] Related Publications
The human EphA3 gene was discovered in a pre-B acute lymphoblastic leukemia (pre-B-ALL) using the EphA3-specific monoclonal antibody (mAb), IIIA4, which binds and activates both human and mouse EphA3. We use two models of human pre-B-ALL to examine EphA3 function, demonstrating effects on pre-B-cell receptor signaling. In therapeutic targeting studies, we demonstrated antitumor effects of the IIIA4 mAb in EphA3-expressing leukemic xenografts and no antitumor effect in the xenografts with no EphA3 expression providing evidence that EphA3 is a functional therapeutic target in pre-B-ALL. Here we show that the therapeutic effect of the anti-EphA3 antibody was greatly enhanced by adding an α-particle-emitting

Day TF, Mewani RR, Starr J, et al.
Transcriptome and Proteome Analyses of TNFAIP8 Knockdown Cancer Cells Reveal New Insights into Molecular Determinants of Cell Survival and Tumor Progression.
Methods Mol Biol. 2017; 1513:83-100 [PubMed] Related Publications
Tumor necrosis factor-α-inducible protein 8 (TNFAIP8) is the first discovered oncogenic and an anti-apoptotic member of a conserved TNFAIP8 or TIPE family of proteins. TNFAIP8 mRNA is induced by NF-kB, and overexpression of TNFAIP8 has been correlated with poor prognosis in many cancers. Downregulation of TNFAIP8 expression has been associated with decreased pulmonary colonization of human tumor cells, and enhanced sensitivities of tumor xenografts to radiation and docetaxel. Here we have investigated the effects of depletion of TNFAIP8 on the mRNA, microRNA and protein expression profiles in prostate and breast cancers and melanoma. Depending on the tumor cell type, knockdown of TNFAIP8 was found to be associated with increased mRNA expression of several antiproliferative and apoptotic genes (e.g., IL-24, FAT3, LPHN2, EPHA3) and fatty acid oxidation gene ACADL, and decreased mRNA levels of oncogenes (e.g., NFAT5, MALAT1, MET, FOXA1, KRAS, S100P, OSTF1) and glutamate transporter gene SLC1A1. TNFAIP8 knockdown cells also exhibited decreased expression of multiple onco-proteins (e.g., PIK3CA, SRC, EGFR, IL5, ABL1, GAP43), and increased expression of the orphan nuclear receptor NR4A1 and alpha 1 adaptin subunit of the adaptor-related protein complex 2 AP2 critical to clathrin-mediated endocytosis. TNFAIP8-centric molecules were found to be predominately implicated in the hypoxia-inducible factor-1α (HIF-1α) signaling pathway, and cancer and development signaling networks. Thus TNFAIP8 seems to regulate the cell survival and cancer progression processes in a multifaceted manner. Future validation of the molecules identified in this study is likely to lead to new subset of molecules and functional determinants of cancer cell survival and progression.

Swords RT, Greenberg PL, Wei AH, et al.
KB004, a first in class monoclonal antibody targeting the receptor tyrosine kinase EphA3, in patients with advanced hematologic malignancies: Results from a phase 1 study.
Leuk Res. 2016; 50:123-131 [PubMed] Related Publications
EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.

Peng J, Wang Q, Liu H, et al.
EPHA3 regulates the multidrug resistance of small cell lung cancer via the PI3K/BMX/STAT3 signaling pathway.
Tumour Biol. 2016; 37(9):11959-11971 [PubMed] Free Access to Full Article Related Publications
Multidrug resistance (MDR) is a major obstacle to the treatment of small cell lung cancer (SCLC). EPHA3 has been revealed to be the most frequently mutated Eph receptor gene in lung cancer with abnormal expression. Growing evidence indicates that the signaling proteins of EPHA3 downstream, including PI3K, BMX and STAT3, play crucial roles in tumorigenesis and cancer progression. To explore the possible role of EPHA3 in MDR, we assessed the influence of EPHA3 on chemoresistance, cell cycle, apoptosis, and tumor growth, as well as the relationship between EPHA3 and the expression of PI3K, BMX, and STAT3 in SCLC. We observed that overexpression of EPHA3 in SCLC cells decreased chemoresistance by increasing apoptosis and inducing G0/G1 arrest, accompanied by reduced phosphorylation of PI3K/BMX/STAT3 signaling pathway. Knockdown of EPHA3 expression generated a resistant phenotype of SCLC, as a result of decreased apoptosis and induced G2/M phase arrest. And re-expression of EPHA3 in these cells reversed the resistant phenotype. Meanwhile, increased phosphorylation of PI3K/BMX/STAT3 signaling pathway was observed in these cells with EPHA3 deficiency. Notably, both PI3K inhibitor (LY294002) and BMX inhibitor (LFM-A13) impaired the chemoresistance enhanced by EPHA3 deficiency in SCLC cell lines. Furthermore, EPHA3 inhibited growth of SCLC cells in vivo and was correlated with longer overall survival of SCLC patients. Thus, we first provide the evidences that EPHA3 is involved in regulating the MDR of SCLC via PI3K/BMX/STAT3 signaling and may be a new therapeutic target in SCLC.

Li M, Yang C, Liu X, et al.
EphA3 promotes malignant transformation of colorectal epithelial cells by upregulating oncogenic pathways.
Cancer Lett. 2016; 383(2):195-203 [PubMed] Related Publications
Ephrin Type-A Receptor 3 (EphA3) belongs to the ephrin receptor subfamily of the protein tyrosine kinase family, and plays an important role in embryogenesis and neurogenesis. This study aimed to investigate the role of EphA3 in promoting malignant transformation of colorectal epithelial cells, and explore underlying molecular mechanisms. Colorectal cancer tissue specimens from 68 patients were analyzed for EphA3 expression. EphA3 expression levels were manipulated in rat colon epithelial cell lines. We found that EphA3 expression level in tumor tissues was associated with patient age (P = 0.015), tumor differentiation (P = 0.001), and lymph node metastasis (P = 0.039). Overexpression of EphA3 and its constitutively active mutants promoted colony formation, migration and invasion, and tumorigenicity of colon epithelial cells in nude mice. The cDNA and lncRNA microarray profiling data revealed that differentially expressed genes and lncRNAs in EphA3 or mutant-transfected cells were associated with cell proliferation, invasion and angiogenesis. Our findings reveal the mechanisms underlying the oncogenic activities of EphA3 in colorectal cells, which could provide novel targets for the prevention, early diagnosis, and treatment of colorectal cancer.

Wang X, Xu H, Cao G, et al.
Loss of EphA3 Protein Expression Is Associated With Advanced TNM Stage in Clear-Cell Renal Cell Carcinoma.
Clin Genitourin Cancer. 2017; 15(2):e169-e173 [PubMed] Related Publications
BACKGROUND: Erythropoietin-producing hepatocellular carcinoma (Eph) receptors constitute the largest family of receptor tyrosine kinases. Ephs and their ligands ephrins play an important role in development and carcinogenesis. The expression of EphA3, an Eph family member, has been investigated in a variety of human cancers, with mixed results. High levels of EphA3 protein expression have been reported in colorectal, prostate, and gastric cancers, whereas loss of protein expression has been reported in lung and hematopoietic cancers. EphA3 expression in clear-cell renal cell carcinoma (ccRCC) and its association with clinicopathological parameters has not previously been examined. The aim of this study was to determine the cancerous value of EphA3 protein expression in patients with ccRCC.
MATERIALS AND METHODS: This study included 68 patients with ccRCC. EphA3 protein expression was examined in ccRCC tissue samples using immunohistochemistry and a specific polyclonal antibody, and the correlation between EphA3 expression and clinicopathological parameters was subsequently evaluated.
RESULTS: High EphA3 protein expression was observed in all normal renal tubules. In the 68 ccRCC patient samples examined, EphA3 protein expression was detected in 19 cases (27.9%) and undetectable in 49 cases (72.1%). EphA3 protein expression was significantly associated with tumor diameter (P = .016) and tumor, node metastases stage (P = .029). No significant association between protein expression and sex (P = .387), age (P = .727), or nuclear grade (P = .243) was found.
CONCLUSION: Ourdata indicate that EphA3 protein expression is reduced in ccRCC, suggesting the possibility that this receptor functions as a tumor suppressor in this disease.

Efazat G, Novak M, Kaminskyy VO, et al.
Ephrin B3 interacts with multiple EphA receptors and drives migration and invasion in non-small cell lung cancer.
Oncotarget. 2016; 7(37):60332-60347 [PubMed] Free Access to Full Article Related Publications
Ephrin receptors (Ephs) are reported to control metastatic signaling of non-small cell lung cancer (NSCLC) and other tumors. Here we show for the first time that blocking expression of the Eph ligand Ephrin B3 inhibits NSCLC cell migration and invasion. We demonstrate that Ephrin B3 directly binds the EphAs EphA2, EphA3, EphA4, and EphA5. EphA2 Ser897 was previously shown to drive migration propensity of tumor cells and our study reveals that EphA2 stays phosphorylated on Ser897 in the Ephrin B3/EphA2 complex in NSCLC cells of different histology. Moreover, we report that within such Ephrin B3/EphA2 complex both Akt Ser 129 and p38MAPK are found indicating a potential to drive migration/proliferation. We also found the EMT marker E-cadherin expression to be maintained or increased upon Ephrin B3 blockade in NSCLC cells. Expression of Ephrin B3 was furthermore analyzed in a cohort of NSCLC stage IA-IB cases (n=200) alongside EphA2 and Ephrin A1. We found that Ephrin B3 was concomitantly expressed with EphA2 and Ephrin A1 with higher Ephrin B3 levels found in non-squamous than in squamous tumors, whereas EphA2 was higher expressed in well-differentiated than in low-differentiated tumors. In the entire NSCLC cohort, Ephrin B3 expression was not linked to patient survival, whereas a high EphA2 expression was associated with improved survival (p=0.03). In conclusion, we show that blocking Ephrin B3 expression inhibits NSCLC proliferation-, migration- and invasion capacity which calls for further studies on interference with Ephrin B3 as a possible therapeutic avenue in this tumor malignancy.

Ferluga S, Tomé CM, Herpai DM, et al.
Simultaneous targeting of Eph receptors in glioblastoma.
Oncotarget. 2016; 7(37):59860-59876 [PubMed] Free Access to Full Article Related Publications
Eph tyrosine kinase receptors are frequently overexpressed and functional in many cancers, and they are attractive candidates for targeted therapy. Here, we analyzed the expression of Eph receptor A3, one of the most up-regulated factors in glioblastoma cells cultured under tumorsphere-forming conditions, together with EphA2 and EphB2 receptors. EphA3 was overexpressed in up to 60% of glioblastoma tumors tested, but not in normal brain. EphA3 was localized in scattered areas of the tumor, the invasive ring, and niches near tumor vessels. EphA3 co-localized with macrophage/leukocyte markers, suggesting EphA3 expression on tumor-infiltrating cells of bone marrow origin. We took advantage of the fact that ephrinA5 (eA5) is a ligand that binds EphA3, EphA2 and EphB2 receptors, and used it to construct a novel targeted anti-glioblastoma cytotoxin. The eA5-based cytotoxin potently and specifically killed glioblastoma cells with an IC50 of at least 10-11 M. This and similar cytotoxins will simultaneously target different compartments of glioblastoma tumors while mitigating tumor heterogeneity.

Suksawat M, Techasen A, Namwat N, et al.
Upregulation of endothelial nitric oxide synthase (eNOS) and its upstream regulators in Opisthorchis viverrini associated cholangiocarcinoma and its clinical significance.
Parasitol Int. 2017; 66(4):486-493 [PubMed] Related Publications
Endothelial nitric oxide synthase (eNOS) is an isoform of the enzyme nitric oxide synthase (NOS) which is constitutively expressed in endothelial cells and plays important roles in vasodilation. We previously reported the importance of eNOS activation in cholangiocarcinoma (CCA) tissues and cell lines. The present study aims to investigate the relative abundance of eNOS and phosphorylated eNOS (P-eNOS) and their upstream regulators VEGFR3, VEGFC, EphA3 and ephrin-A1, in the Opisthorchis viverrini (Ov)/N-nitrosodimethylamine (NDMA)-induced hamster CCA model and in human CCA by semiquantitative immunohistochemical analysis of the relevant tissues. Results from the hamster model suggested an increase in eNOS and P-eNOS and upstream regulators during CCA genesis. In human CCA, high immunohistochemical staining intensity of all investigated proteins was associated with the presence of metastasis. A pairwise analysis of the staining data for eNOS and its upstream regulators showed that a concurrent increase in eNOS/VEGFR3, eNOS/ephrin-A1, eNOS/VEGFC and eNOS/EphA3 was significantly associated with metastasis. An increase in eNOS/VEGFR3, eNOS/ephrin-A1 was also associated with non-papillary type CCA. Additionally, an increase in eNOS and P-eNOS was significantly correlated with a high micro-vessel level (P=0.04). Our results indicate that the development of CCA involves upregulation of eNOS and P-eNOS and their regulators. This may drive angiogenesis and metastasis in CCA.

Hood G, Laufer-Amorim R, Fonseca-Alves CE, Palmieri C
Overexpression of Ephrin A3 Receptor in Canine Prostatic Carcinoma.
J Comp Pathol. 2016 Feb-Apr; 154(2-3):180-5 [PubMed] Related Publications
Ephrin A3 (EphA3), a member of the ephrin receptor tyrosine kinase family, is involved in a variety of functions in normal cells, especially during embryonic development, and alterations in its expression profile have been observed in several human cancers. However, there are no reports of the expression of EphA3 in normal, hyperplastic or neoplastic canine prostate tissue or in other types of canine tumours. Six normal, 15 hyperplastic and 21 neoplastic canine prostates were examined immunohistochemically with a polyclonal antibody specific for human EphA3. The percentage of positive cells in all prostatic carcinomas was increased, with a mean of 89.28 ± 5.18% compared with normal (9.17 ± 6.72%) and hyperplastic prostates (20.00 ± 8.28%). EphA3 expression was not correlated with the histological subtypes of prostate cancer or with the Gleason score. The increase in EphA3 expression in canine prostatic carcinomas suggests the involvement of this receptor in prostatic carcinogenesis and its potential use as a target for new therapeutic strategies.

Cañas A, López-Sánchez LM, Peñarando J, et al.
Altered S-nitrosothiol homeostasis provides a survival advantage to breast cancer cells in HER2 tumors and reduces their sensitivity to trastuzumab.
Biochim Biophys Acta. 2016; 1862(4):601-610 [PubMed] Related Publications
The monoclonal antibody trastuzumab against HER2/neu, which is overexpressed in 15-20% of breast cancers, has clinical efficacy but many patients do not respond to initial treatment or develop resistance during treatment. Nitric oxide (NO) regulates cell signaling by targeting specific cysteine residues in proteins, forming S-nitrosothiols (SNO) in a process known as S-nitrosylation. We previously reported that molecular characteristics in breast cancer may dictate the tumor response to impaired SNO homeostasis. In the present study, we explored the role of SNO homeostasis in HER2 breast tumors. The antiproliferative action of trastuzumab in HER2-overexpressing BT-474 and SKBR-3 cells was suppressed when S-nitrosoglutathione reductase (GSNOR/ADH5) activity, which plays a key role in SNO homeostasis, was specifically inhibited with the pyrrole derivative compound N6022. Moreover, GSNOR inhibition restored the activation of survival signaling pathways involved in the resistance to anti-HER2 therapies (AKT, Src and c-Abl kinases and TrkA/NRTK1, TrkB/NRTK2, EphA1 and EphA3 receptors) and reduced the apoptotic effect of trastuzumab. Accordingly, GSNOR inhibition augmented the S-nitrosylation of apoptosis-related proteins, including Apaf-1, pSer73/63 c-Jun, calcineurin subunit α and HSF1. In agreement with in vitro data, immunohistochemical analyses of 51 breast tumors showed that HER2 expression was associated with lower expression of GSNOR protein. Moreover, gene expression analysis confirmed that high ADH5/GSNOR gene expression was associated with high patient survival rates in HER2 tumors. In conclusion, our data provide evidence of molecular mechanisms contributing to the progression of HER2+ breast cancers and could facilitate the development of therapeutic options to counteract resistance to anti-HER2 therapies.

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