Gene Summary

Gene:EFNB3; ephrin B3
Aliases: EFL6, EPLG8, LERK8
Summary: EFNB3, a member of the ephrin gene family, is important in brain development as well as in its maintenance. Moreover, since levels of EFNB3 expression were particularly high in several forebrain subregions compared to other brain subregions, it may play a pivotal role in forebrain function. The EPH and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, particularly in the nervous system. EPH Receptors typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin ligands and receptors have been named by the Eph Nomenclature Committee (1997). Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are similarly divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 30 August, 2019


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 30 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: EFNB3 (cancer-related)

Dominguez-Brauer C, Hao Z, Elia AJ, et al.
Mule Regulates the Intestinal Stem Cell Niche via the Wnt Pathway and Targets EphB3 for Proteasomal and Lysosomal Degradation.
Cell Stem Cell. 2016; 19(2):205-216 [PubMed] Free Access to Full Article Related Publications
The E3 ubiquitin ligase Mule is often overexpressed in human colorectal cancers, but its role in gut tumorigenesis is unknown. Here, we show in vivo that Mule controls murine intestinal stem and progenitor cell proliferation by modulating Wnt signaling via c-Myc. Mule also regulates protein levels of the receptor tyrosine kinase EphB3 by targeting it for proteasomal and lysosomal degradation. In the intestine, EphB/ephrinB interactions position cells along the crypt-villus axis and compartmentalize incipient colorectal tumors. Our study thus unveils an important new avenue by which Mule acts as an intestinal tumor suppressor by regulation of the intestinal stem cell niche.

Zhu H, Yang M, Zhang H, et al.
Genome-wide association pathway analysis to identify candidate single nucleotide polymorphisms and molecular pathways for gastric adenocarcinoma.
Tumour Biol. 2015; 36(7):5635-9 [PubMed] Related Publications
To demonstrate candidate single nucleotide polymorphisms that might affect susceptibility to gastric adenocarcinoma as well as their potential mechanisms and pathway hypotheses, we performed a genome-wide association study dataset of gastric adenocarcinoma. Our study included 472,342 single nucleotide polymorphisms from 2766 cases of gastric cardia adenocarcinoma cases and 11,013 subjects from north central China as control groups. The identify candidate causal SNPs and pathways (ICSNPathway) analysis was employed to identify 13 candidate single nucleotide polymorphisms, nine genes, and 15 pathways. The top three candidate SNPs were rs3765524 (-log10(p) = 8.556), rs2274223 (-log10(p) = 8.633), and rs2076472 (-log10(p) = 3.205). The strongest mechanism involved the modulation of rs4745 and rs12904, thereby affecting their regulatory roles in ephrin receptor binding (p = 0.001; FDR = 0.005). The second strongest hypothetical biological mechanism was that rs932972 and rs1052177 alters the regulatory role of the glycolysis pathway (p < 0.001; FDR = 0.013). The most significant pathway was the regulation of the ephrin receptor binding pathway, which involved EFNA1, TIAM1, EFNA5, EFNB2, and EFNB3.

Nevo I, Woolard K, Cam M, et al.
Identification of molecular pathways facilitating glioma cell invasion in situ.
PLoS One. 2014; 9(11):e111783 [PubMed] Free Access to Full Article Related Publications
Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion. In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC) xenograft model to explore gene expression changes in situ in Invading Glioma Cells (IGCs) compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT) processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy.

Wang SS, Hsiao R, Limpar MM, et al.
Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin.
Int J Mol Med. 2014; 33(1):35-42 [PubMed] Free Access to Full Article Related Publications
In the present study, we investigated the anticancer effects of the mitochondrial inhibitors, metaiodobenzylguanidine (MIBG), metformin and phenformin. 131I-MIBG has been used for scintigraphic detection and the targeted radiotherapy of neuroblastoma (NB), a pediatric malignancy. Non-radiolabeled MIBG has been reported to be cytotoxic to NB cells in vitro and in vivo. However, the mechanisms behind its growth suppressive effects have not yet been fully elucidated. Metformin and phenformin are diabetes medications that are being considered in anticancer therapeutics. We investigated the anticancer mechanisms of action of MIBG and metformin in NB. Our data revealed that both drugs suppressed NB cell growth and that the combination drug treatment was more potent. MIBG reduced MYCN and MYC expression in MYCN-amplified and non-MYCN-amplified NB cells in a dose- and time-dependent manner. Metformin was less effective than MIBG in destabilizing MYC/MYCN. The treatment of NB cells with metformin or MIBG resulted in an increased expression of genes encoding biomarkers for favorable outcome in NB [(ephrin (EFN)B2, EFNB3, EPH receptor B6 (EPHB6), neurotrophic tyrosine kinase, receptor, type 1 (NTRK1), CD44 and Myc-interacting zinc finger protein (MIZ-1)] and tumor suppressor genes [(early growth response 1 (EGR1), EPH receptor A2 (EPHA2), growth arrest and DNA-damage-inducible, beta (GADD45B), neuregulin 1 (NRG1), TP53 apoptosis effector (PERP) and sel-1 suppressor of lin-12-like (C. elegans) (SEL1L)]. Accordingly, metformin and MIBG augmented histone H3 acetylation in these cells. Phenformin also exhibited histone modification and was more effective than metformin in destabilizing MYC/MYCN in NB cells. Our data suggest that the destabilization of MYC/MYCN by MIBG, metformin and phenformin and their effects on histone modification are important mechanisms underlying their anticancer effects.

Baniwal SK, Chimge NO, Jordan VC, et al.
Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner.
PLoS One. 2014; 8(6):e62361 [PubMed] Free Access to Full Article Related Publications
Prolactin-induced Protein (PIP), an aspartyl protease unessential for normal mammalian cell function, is required for the proliferation and invasion of some breast cancer (BCa) cell types. Because PIP expression is particularly high in the Luminal A BCa subtype, we investigated the roles of PIP in the related T47D BCa cell line. Nucleic acid and antibody arrays were employed to screen effects of PIP silencing on global gene expression and activation of receptor tyrosine kinases (RTKs), respectively. Expression of PIP-stimulated genes, as defined in the T47D cell culture model, was well correlated with the expression of PIP itself across a cohort of 557 mRNA profiles of diverse BCa tumors, and bioinformatics analysis revealed cJUN and cMYC as major nodes in the PIP-dependent gene network. Among 71 RTKs tested, PIP silencing resulted in decreased phosphorylation of focal adhesion kinase (FAK), ephrin B3 (EphB3), FYN, and hemopoietic cell kinase (HCK). Ablation of PIP also abrogated serum-induced activation of the downstream serine/threonine kinases AKT, ERK1/2, and JNK1. Consistent with these results, PIP-depleted cells exhibited defects in adhesion to fibronectin, cytoskeletal stress fiber assembly and protein secretion. In addition, PIP silencing abrogated the mitogenic response of T47D BCa cells to estradiol (E2). The dependence of BCa cell proliferation was unrelated, however, to estrogen signaling because: 1) PIP silencing did not affect the transcriptional response of estrogen target genes to hormone treatment, and 2) PIP was required for the proliferation of tamoxifen-resistant BCa cells. Pharmacological inhibition of PIP may therefore serve the bases for both augmentation of existing therapies for hormone-dependent tumors and the development of novel therapeutic approaches for hormone-resistant BCa.

Ståhl S, Kaminskyy VO, Efazat G, et al.
Inhibition of Ephrin B3-mediated survival signaling contributes to increased cell death response of non-small cell lung carcinoma cells after combined treatment with ionizing radiation and PKC 412.
Cell Death Dis. 2013; 4:e454 [PubMed] Free Access to Full Article Related Publications
Radiation therapy is frequently used to treat non-small cell lung cancers (NSCLCs). We have previously shown that a combination of ionizing radiation (IR) and the staurosporine analog PKC 412, but not Ro 31-8220, increases cell death in NSCLC cells. To identify genes involved in the enhancement of cell death, a total gene profiling in response to co-administration of (i) PKC 412 with IR, or (ii) Ro 31-8220 with IR was implemented. These combined treatments caused upregulation of 140 and 179 genes and downregulation of 253 and 425 genes, respectively. Certain genes were selected and verified by real-time quantitative PCR and, of these genes, robust suppression of Ephrin B3 expression was suggested as a possible cell death-inducing mechanism of combined treatment with IR and PKC 412. Indeed, silencing of Ephrin B3 using siRNA in NSCLC cells resulted in a major alteration of their morphology with an elongated phenotype, decreased proliferation and increased cell death signaling. Moreover, silencing of Ephrin B3 in combination with IR caused a decrease in IR-mediated G(2)-arrest, induced cellular senescence, inhibited MAPK ERK and p38 phosphorylation, and caused an upregulation of p27(kip1) expression. Finally, silencing of Ephrin B3 in combination with IR sensitized U-1810 cells to IR-induced apoptosis. In conclusion, we identify and describe Ephrin B3 as a putative signaling molecule involved in the response of NSCLC cells to combined treatment with PKC 412 and ionizing radiation.

Davidson B, Abeler VM, Hellesylt E, et al.
Gene expression signatures differentiate uterine endometrial stromal sarcoma from leiomyosarcoma.
Gynecol Oncol. 2013; 128(2):349-55 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Endometrial stromal sarcoma (ESS) and leiomyosarcoma (LMS) are the two most common uterine sarcomas, but both are rare tumors. The aim of the present study was to compare the global gene expression patterns of ESS and LMS.
METHODS: Gene expression profiles of 7 ESS and 13 LMS were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry.
RESULTS: Unsupervised hierarchical clustering using all 54,675 genes in the array separated ESS from LMS samples. We identified 549 unique probes that were significantly differentially expressed in the two malignancies by greater than 2-fold with 1% FDR cutoff using one-way ANOVA with Benjamini-Hochberg correction, of which 336 and 213 were overexpressed in ESS and LMS, respectively. Genes overexpressed in ESS included SLC7A10, EFNB3, CCND2, ECEL1, ITM2A, NPW, PLAG1 and GCGR. Genes overexpressed in LMS included CDKN2A, FABP3, TAGLN, JPH2, GEM, NAV2 and RAB23. The top 100 genes overexpressed in LMS included those coding for myosin light chain and caldesmon, but not the genes coding for desmin or actin. CD10 was not overexpressed in ESS. Results for selected genes were validated by quantitative real-time PCR and immunohistochemistry.
CONCLUSIONS: We present the first study in which gene expression profiling was shown to distinguish between ESS and LMS. The molecular signatures unique to each of these malignancies may aid in expanding the diagnostic battery for their differentiation, and may provide a molecular basis for prognostic studies and therapeutic target discovery.

Schauer MC, Stoecklein NH, Theisen J, et al.
The simultaneous expression of both ephrin B3 receptor and E-cadherin in Barrett`s adenocarcinoma is associated with favorable clinical staging.
Eur J Med Res. 2012; 17:10 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In intestinal epithelium, tyrosine kinase receptor Ephrin B3 (Eph B3) maintains the architecture of the crypt-villus axis by repulsive interaction with its ligand ephrin-B1. While loss of Eph B3 is linked to colorectal cancer initiation, overexpression of Eph B3 in cancer cell lines inhibits growth and induces functional changes with decreased mesenchymal and increased epithelial markers. In order to study this tumor suppressor activity of Eph B3 in esophageal adenocarcinoma we analyzed the simultaneous expression of Eph B3 and E-cadherin in both the healthy esophagus and in Barrett's carcinoma.
METHODS: Simultaneous expression of Eph B3 and E-cadherin was investigated in samples from 141 patients with Barrett's carcinoma and from 20 healthy esophagi using immunhistology and quantitative PCR. Results from healthy squamous epithelium, Barrett's metaplasia and staging-specific esophageal adenocarcinoma were correlated.
RESULTS: A significantly reduced E-cadherin mRNA expression could be detected in adenocarcinoma compared to dysplasia. The immunhistological activity of E-cadherin and Eph B3 was reduced in adenocarcinoma compared to dysplasia or healthy esophageal mucosa. The intracellular E-cadherin distribution changed significantly from the cytoplasm to the membrane, when the Eph receptor was simultaneously expressed. Simultaneous expression of E-cadherin and Eph B3 showed a significant inverse correlation to tumor stage.
CONCLUSIONS: We present novel evidence of the tumor suppressor activity of Eph B3 in esophageal adenocarcinoma possibly due to the impact on redistribution of cellular E-cadherin to the membrane. Our results suggest that this effect might play a role in the dysplasia-adenocarcinoma sequence, the infiltrative growth pattern and the development of lymph node metastases.

Schauer M, Knoefel WT
Neoadjuvant chemotherapy in Barrett's carcinoma - prognosis and response prediction.
Anticancer Res. 2010; 30(4):1065-70 [PubMed] Related Publications
In spite of endoscopic surveillance programs, 90% of patients initially presenting with Barrett's carcinoma have locally advanced disease. In these patients, preoperative chemotherapy increases the chance of a curative resection in responding patients. Unfortunately, response occurs in only 50% of patients after chemotherapy with cisplatin, 5-fluorouracil and leucovorin. Response prediction seems to be possible by measuring metabolic activity by positron emission tomography (PET) scan. Differentiation of responders from non-responders even before starting chemotherapy might be possible using microarray technology and immunhistology in tumour biopsies. A pattern of at least two-fold differentially regulated genes comparing responding and non-responding oesophageal adenocarcinomas was identified. The strongest difference can be seen for tumour necrosis factor, polyribonucleotide nucleotidyltransferase and the ephrin-B3-receptor. In conclusion, our experience suggests that it may be possible to characterize patients responding to chemotherapy by PET two weeks after starting the chemotherapy or even before treatment using customized microarray analysis.

Schluth-Bolard C, Sanlaville D, Labalme A, et al.
17p13.1 microdeletion involving the TP53 gene in a boy presenting with mental retardation but no tumor.
Am J Med Genet A. 2010; 152A(5):1278-82 [PubMed] Related Publications
We report on the diagnosis of a 17p13.1 deletion in a 10-year-old boy. The patient presented with mild developmental delay, facial dysmorphism, joint hyperlaxity, pes planus, hypermetropia, hearing loss, and achromic patches following the Blaschko's lines on the right part of the thorax. Chromosome R-banding was normal. Array CGH using a 244 K oligonucleotide array showed a homogeneous de novo 17p13.1 microdeletion of 400 kb involving TP53 and 25 other genes, including genes involved in brain function (EFNB3, FXR2). To our knowledge, six patients presenting with a constitutional 17p13.1 microdeletion involving the TP53 gene have been reported. We discuss the phenotype of this microdeletion and the genetic counseling issues, especially regarding the risk of cancer associated with the deletion of the TP53 gene.

Schauer M, Janssen KP, Rimkus C, et al.
Microarray-based response prediction in esophageal adenocarcinoma.
Clin Cancer Res. 2010; 16(1):330-7 [PubMed] Related Publications
PURPOSE: In locally advanced (uT(3), N(+)) adenocarcinomas of the esophagus, neoadjuvant chemotherapy improves patient outcome. However, only a subgroup of patients responds. Therefore, in the present study, we evaluated whether the response to neoadjuvant chemotherapy can be predicted by a pretreatment tumor biopsy analysis.
EXPERIMENTAL DESIGN: Biopsies of 47 patients with locally advanced (uT(3), N(+)) adenocarcinoma of the esophagus were obtained during primary staging. All patients underwent neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and leucovorin and subsequent resection of the esophagus. Biopsies were used for microarray analysis. The predominance of tumor cells within the specimens was >70%. Affymetrix U133 plus 2.0 gene chips with 54675 probe sets were used. A statistical comparison of patients responding to chemotherapy versus nonresponding patients was done. All patients were examined with immunohistology against Ephrin B3 receptor and Ki-67.
RESULTS: A total of 86 genes were at least 2-fold differentially regulated comparing responding with nonresponding adenocarcinomas of the esophagus. The predominant genes encoded for the regulation of the cell cycle, transduction, translation, cell-cell interaction, cytoskeleton, and the signal transduction. The strongest difference was seen for the Ephrin B3 receptor. This result could be confirmed by immunhistology. A statistical significant correlation between the Ephrin B3 receptor, chemotherapy response, pathologic staging, and grading could be shown.
CONCLUSIONS: There were significant differences in the gene profile between patients with adenocarcinoma of the esophagus responding to neoadjuvant chemotherapy compared with nonresponding patients. This suggests that it could be possible to characterize patients responding to chemotherapy even before starting the treatment using customized microarray analysis.

Peirce SK, Findley HW
High level MycN expression in non-MYCN amplified neuroblastoma is induced by the combination treatment nutlin-3 and doxorubicin and enhances chemosensitivity.
Oncol Rep. 2009; 22(6):1443-9 [PubMed] Related Publications
MYCN gene amplification is a negative prognostic indicator in neuroblastoma and high level MycN expression in Stage IV neuroblastoma is generally a hallmark of poor patient outcome. However, high level expression of the MycN protein in neuroblastoma cells lacking MYCN amplification suppresses growth and drives apoptosis; this, in part, explains the absence of clinical observations of high level MycN in neuroblastoma lacking MYCN amplification. In the current study, we found that combination treatment with nutlin-3 and doxorubicin upregulated MycN expression in non-MYCN-amplified neuroblastoma cells at both the protein and mRNA levels. The induced expression of MycN in non-MYCN-amplified cells inhibited cell proliferation and increased apoptosis. MycN induction also upregulated p53, p21 and Bax protein levels, as well as mRNA levels for the positive neuroblastoma prognostic factors CD44 and EFNB3. Blocking MycN reversed these effects. These results were corroborated by findings using a MycN-inducible system in SHEP cells, another MYCN non-amplified neuroblastoma cell line. Our results indicate that doxorubicin/nutlin-3 combination treatment both induces expression of MycN in a non-MYCN-amplified background and sensitizes neuroblastoma cells to chemotherapy. These findings support the idea that induction of MycN in non-MYCN-amplified cells drives neuroblastoma cells toward apoptosis and suggest that combination nutlin-3/doxorubicin treatment may be clinically important.

Ikegaki N, Gotoh T, Kung B, et al.
De novo identification of MIZ-1 (ZBTB17) encoding a MYC-interacting zinc-finger protein as a new favorable neuroblastoma gene.
Clin Cancer Res. 2007; 13(20):6001-9 [PubMed] Related Publications
PURPOSE: Neuroblastoma is a childhood cancer that exhibits either a favorable or an unfavorable phenotype. Favorable neuroblastoma genes (EPHB6, EFNB2, EFNB3, NTRK1, and CD44) are genes whose high-level expression predicts favorable neuroblastoma disease outcome. Accordingly, the forced expression of these genes or their reactivation by gene silencing inhibitors in unfavorable neuroblastoma cells results in suppression of tumor growth and metastases. This study was undertaken to design an experimental strategy to identify additional favorable neuroblastoma genes.
EXPERIMENTAL DESIGN: Favorable neuroblastoma gene candidates were first identified by gene expression profiling analysis on IMR5 neuroblastoma cells treated with inhibitors of DNA methylation and histone deacetylase against the untreated control cells. Among the candidates, we focused on MIZ-1, which encodes a MYC-interacting zinc-finger protein, because it is known to enhance the expression of growth suppressive genes, such as CDKN1A.
RESULTS: High-level MIZ-1 expression was associated with favorable disease outcome of neuroblastoma (P = 0.0048). Forced MIZ-1 expression suppressed in vitro growth of neuroblastoma cell lines. High MIZ-1 expression was correlated with the small-size neuroblastoma xenografts treated with gene silencing inhibitors or a glucocorticoid. In addition, forced MIZ-1 expression enhanced the expression of CD44 and EFNB2 in neuroblastoma cell lines in vitro. Furthermore, MIZ-1 expression was positively correlated with the expression of favorable neuroblastoma genes (EFNB2, EFNB3, EPHB6, and NTRK1) in the human neuroblastoma xenograft therapeutic models.
CONCLUSION: MIZ-1 is a new favorable neuroblastoma gene, which may directly or indirectly regulate the expression of other favorable neuroblastoma genes.

Castellano G, Reid JF, Alberti P, et al.
New potential ligand-receptor signaling loops in ovarian cancer identified in multiple gene expression studies.
Cancer Res. 2006; 66(22):10709-19 [PubMed] Related Publications
Based on the hypothesis that gene products involved in the same biological process would be coupled at transcriptional level, a previous study analyzed the correlation of the gene expression patterns of ligand-receptor (L-R) pairs to discover potential autocrine/paracrine signaling loops in different cancers (Graeber and Eisenberg. Nat Genet 2001; 29:295). By refining the starting database, a list of 511 L-R pairs was compiled, combined to eight data sets from a single pathology, epithelial ovarian cancer, and examined as a proof-of-principle of the statistical and biological validity of the correlation of the L-R gene expression patterns in cancer. Analysis revealed a Bonferroni-corrected significant correlation of 105 L-R pairs in at least one data set and, by systematic analysis, identified 39 more frequently correlated L-R pairs, 7 of which were already biologically confirmed. In four data sets examined for an L-R correlation associated with patient survival time, 15 L-R pairs were significantly correlated in short surviving patients in two of the data sets. Immunohistochemical analysis of one of the newly identified correlated L-R pairs (i.e., EFNB3-EPHB4) revealed the correlated expression of ephrin-B3 and EphB4 proteins in 45 of 55 epithelial ovarian tumor samples (P < 0.0001). Together, these data not only support the validity of cross-comparison analysis of gene expression data because known and expected correlations were confirmed but also point to the promise of such analysis in identifying new L-R signaling loops in cancer.

Valladares A, Hernández NG, Gómez FS, et al.
Genetic expression profiles and chromosomal alterations in sporadic breast cancer in Mexican women.
Cancer Genet Cytogenet. 2006; 170(2):147-51 [PubMed] Related Publications
Breast cancer is the second-leading cause of death among Mexican women >35 years of age. At the molecular level, changes in many genetic pathways have been reported to be associated with this neoplasm. To analyze these changes, we determined gene expression profiles and chromosomal structural alterations in tumors from Mexican women. We obtained mRNA to identify expression profiles with microarray technology, and DNA to determine amplifications and deletions, in 10 fresh sporadic breast tumor biopsies without treatment, as well as in 10 nonaffected breast tissues. Expression profiles were compared with genetic changes observed by comparative genomic hybridization (CGH). We compared the expression profiles against the structural alterations from the studied genes by means of microarrays; at least 17 of these genes correlated with DNA copy number alterations. We found that the following genes were overexpressed: LAMC1, PCTK3, CCNC, CCND1, FGF3, PCTK2, L1CAM, BGN, and PLXNB3 (alias PLEXR). Underexpressed genes included CASP9, FGR, TP73, HSPG2, and ERCC1; genes turned off included FRAP1, EPHA2 (previously ECK), IL12A, E2F5, TNFRSF10B, TNFRSF10A, EFNB3, and BCL2. The results will allow us, in the near future, to outline genes that could serve as diagnostic, prognostic, or target therapy markers for the Mexican population.

Nakada M, Drake KL, Nakada S, et al.
Ephrin-B3 ligand promotes glioma invasion through activation of Rac1.
Cancer Res. 2006; 66(17):8492-500 [PubMed] Related Publications
Eph receptor tyrosine kinases are involved in nervous system development. Eph ligands, termed ephrins, are transmembrane proteins that bind to Eph receptors, the mutual activation of which causes repulsive effects in reciprocally contacting cells. Previously, we showed that overexpression of EphB2 in glioma cells increases cell invasion. Here, expression profiles of ephrin-B family members were determined in four glioma cell lines and in invading glioblastoma cells collected by laser capture microdissection. Ephrin-B3 mRNA was up-regulated in migrating cells of four of four glioma cell lines (1.3- to 1.7-fold) and in invading tumor cells of eight of eight biopsy specimens (1.2- to 10.0-fold). Forced expression of ephrin-B3 in low expressor cell lines (U87, T98G) stimulated cell migration and invasion in vitro and ex vivo, concomitant with tyrosine phosphorylation of ephrin-B3. In high expressor cell lines (U251, SNB19), ephrin-B3 colocalized with Rac1 to lamellipodia of motile wild-type cells. Cells transfected with ephrin-B3 small interfering RNA (siRNA) showed significant morphologic change and decreased invasion in vitro and ex vivo. Depletion of endogenous ephrin-B3 expression abrogated the increase of migration and invasion induced by EphB2/Fc, indicating increased invasion is dependent on ephrin-B3 activation. Furthermore, using a Rac1-GTP pull-down assay, we showed that ephrin-B3 is associated with Rac1 activation. Reduction of Rac1 by siRNA negated the increased invasion by addition of EphB2/Fc. In human glioma specimens, ephrin-B3 expression and phosphorylation correlated with increasing tumor grade. Immunohistochemistry revealed robust staining for phosphorylated ephrin-B and ephrin-B3 in invading glioblastoma cells. These data show that ephrin-B3 expression and signaling through Rac1 are critically important to glioma invasion.

Hoelzinger DB, Mariani L, Weis J, et al.
Gene expression profile of glioblastoma multiforme invasive phenotype points to new therapeutic targets.
Neoplasia. 2005; 7(1):7-16 [PubMed] Free Access to Full Article Related Publications
The invasive phenotype of glioblastoma multiforme (GBM) is a hallmark of malignant process, yet molecular mechanisms that dictate this locally invasive behavior remain poorly understood. Gene expression profiles of human glioma cells were assessed from laser capture-microdissected GBM cells collected from paired patient tumor cores and white matter-invading cell populations. Changes in gene expression in invading GBM cells were validated by quantitative reverse transcription polymerase chain reaction (QRT-PCR) and immunohistochemistry in an independent sample set. QRT-PCR confirmed the differential expression in 19 of 21 genes tested. Immunohistochemical analyses of autotaxin (ATX), ephrin B3, B-cell lymphoma-w (BCLW), and protein tyrosine kinase 2 beta showed them to be expressed in invasive glioma cells. The known GBM markers, insulin-like growth factor binding protein 2 and vimentin, were robustly expressed in the tumor core. A glioma invasion tissue microarray confirmed the expression of ATX and BCLW in invasive cells of tumors of various grades. GBM phenotypic and genotypic heterogeneity is well documented. In this study, we show an additional layer of complexity: transcriptional differences between cells of tumor core and invasive cells located in the brain parenchyma. Gene products supporting invasion may be novel targets for manipulation of brain tumor behavior with consequences on treatment outcome.

Tang XX, Robinson ME, Riceberg JS, et al.
Favorable neuroblastoma genes and molecular therapeutics of neuroblastoma.
Clin Cancer Res. 2004; 10(17):5837-44 [PubMed] Related Publications
PURPOSE AND EXPERIMENTAL DESIGN: Neuroblastoma (NB) is a common pediatric solid tumor that exhibits a striking clinical bipolarity: favorable and unfavorable. Favorable NB genes (EPHB6, EFNB2, EFNB3, NTRK1, and CD44) are genes whose high-level expression predicts favorable NB outcome, and forced expression of these genes inhibits growth of unfavorable NB cells. In this study, we investigated whether favorable NB gene expression could be augmented in unfavorable NB cells by chemical compounds and whether an increased expression of these genes was associated with suppression of NB growth and metastasis.
RESULTS: We found that inhibitors of DNA methylation [5-aza-2'-deoxycytidine (5AdC)], histone deacetylase (HDAC) [4-phenylbutyrate (4PB)], and proteasome (MG262) enhanced the expression of favorable NB genes in NB cell lines and inhibited the growth of these cells in vitro (P < 0.0005). The growth-inhibitory effects of 5AdC and 4PB in vitro were in part due to caspase-dependent cell death and inhibition of DNA synthesis. Administration of 5AdC and/or 4PB also suppressed growth of subcutaneous NB xenografts in nude mice (P < 0.001), which was accompanied by enhanced favorable NB gene expression and an increase in apoptosis. Moreover, 4PB suppressed bone marrow and liver metastases of NB cells in severe combined immunodeficient/Beige mice (P = 0.007 and P = 0.008, respectively). The growth-suppressive activity of HDAC inhibitors on NB was further confirmed by the efficacy of trichostatin A, a potent and specific HDAC inhibitor.
CONCLUSIONS: Collectively, these observations further emphasize the link between the elevated favorable NB gene expression and a benign phenotype of NB.

Sanchez-Carbayo M, Belbin TJ, Scotlandi K, et al.
Expression profiling of osteosarcoma cells transfected with MDR1 and NEO genes: regulation of cell adhesion, apoptosis, and tumor suppression-related genes.
Lab Invest. 2003; 83(4):507-17 [PubMed] Related Publications
The expression patterns of the osteosarcoma cell line U-2 OS, and three derived subclones containing stably transfected MDR1, NEO and MDR1/NEO genes were compared using cDNA microarrays comprising 8976 known genes and expressed sequenced tags. Data provided new insights into three critical issues. First, MDR1 overexpression was associated with altered expression of genes related to several cellular pathways, including (a). drug influx/efflux (eg, dynamin 3), (b). metabolic enzymes (eg, monoamine oxidase A), (c). cell adhesion (eg, EPCAM), (d). apoptotic signaling (eg, I-TRAF), (e). senescence (eg, telomerase RNA binding protein staufen), (f). tumor suppression-related genes (eg, KISS-1 and ephrin B3), and (g). immune system receptors (eg, LENG2). MDR1, EPCAM, and ephrin B3 expression was confirmed by immunohistochemistry. Second, MDR1 transfected cells selected with either doxorubicin or neomycin showed distinct expression profiles that could be related to differential selection. Moreover, hierarchical clustering indicated that cells transfected with MDR1 alone, or cotransfected with NEO, displayed more closely related expression profiles than cells transfected only with NEO. Third, transfection with NEO and selection with neomycin produced a considerable number of expression changes within the cell. This study further elucidates the genetic events associated with MDR1 expression and identifies novel targets associated with multidrug resistance.

Varelias A, Koblar SA, Cowled PA, et al.
Human osteosarcoma expresses specific ephrin profiles: implications for tumorigenicity and prognosis.
Cancer. 2002; 95(4):862-9 [PubMed] Related Publications
BACKGROUND: The molecular mechanisms underlying malignancy of osteosarcoma are unknown. It has been reported that eph receptor protein tyrosine kinases and their ligands, ephrins, are associated with increased tumorigenicity in patients with breast carcinoma and melanoma. The expression and role of eph/ephrins in human osteosarcoma has not yet been characterized.
METHODS: Ephrin-A1, ephrin-A3, ephrin-A4, ephrin-A5, ephrin-B1, ephrin-B2, and ephrin-B3 mRNA expression was examined by reverse transcription polymerase chain reaction analysis in nine specimens of human osteosarcoma tissue and five human osteosarcoma cell lines. Ephrin-B1 protein expression was detected immunohistochemically in human osteosarcoma tissue. Clinicopathologic correlation was made between the osteosarcoma specimens and their ephrin expression profiles.
RESULTS: Normal bone specimens, osteosarcoma tissue specimens, and osteosarcoma cell lines expressed a distinct mRNA profile of ephrin-A1, ephrin-A4, and ephrin-B2. A second mRNA profile that included ephrin-A3, ephrin-A5, and ephrin-B1 was expressed by a subset of tumors. The expression of ephrin-B1 was correlated with a poorer clinical prognosis. Ephrin-B1 protein was expressed by osteosarcoma cells and blood vessels.
CONCLUSIONS: The results of this study suggest that ephrin-B1 expressed by osteosarcoma may be a poor prognostic marker through increased tumorigenicity.

Liu W, Ahmad SA, Jung YD, et al.
Coexpression of ephrin-Bs and their receptors in colon carcinoma.
Cancer. 2002; 94(4):934-9 [PubMed] Related Publications
BACKGROUND: The erythropoietin-producing hepatoma amplified sequence (Eph) family is the largest subfamily of receptor tyrosine kinases (RTKs). The Ephs (receptors) bind to specific cell-bound ligands, called ephrins. The binding of this ligand-receptor system is dependent on cell-cell interactions. The ephrin-Eph system is important in embryologic development and differentiation of the nervous and vascular systems. In the current study, the authors hypothesized that ephrins may play a role in the growth and development of colon carcinoma and may be expressed differentially in normal and malignant colonic tissues.
METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR), Northern Blot analyses, and immunohistochemistry were used to examine 11 colon carcinoma cell lines and 20 human colon carcinoma specimens with adjacent uninvolved mucosa for the expression of EphB and ephrin-B family members.
RESULTS: EphB2, EphB3, and EphB4 mRNA expression and ephrin-B2 mRNA expression was detected in all the cell lines and colon carcinoma specimens examined. Immunohistochemical analysis showed that ephrin-B2 had higher expression in the colon carcinoma specimens studied than in adjacent normal mucosa. Ephrin-B2 and EphB4 most frequently were expressed on the luminal surface of colon carcinoma epithelium.
CONCLUSIONS: The results of the current suggest that the ephrin-Bs are expressed differentially in colon carcinoma and normal mucosa specimens and thus may play a role in the progression of colon carcinoma. Further studies are necessary to determine the functional role of ephrin-Bs in colon carcinoma angiogenesis and growth.

Tang XX, Evans AE, Zhao H, et al.
Association among EPHB2, TrkA, and MYCN expression in low-stage neuroblastomas.
Med Pediatr Oncol. 2001; 36(1):80-2 [PubMed] Related Publications
BACKGROUND: The EPH family is the largest subfamily of receptor protein-tyrosine kinases, consisting of EPHA and EPHB subgroups. Ligands of EPH family receptors are called ephrins, which include ephrin-A and ephrin-B subgroups. We recently found that transcripts encoding the EPHB subgroup (EPHB) and the ephrin-B subgroup (EFNB) were expressed together in neuroblastoma (NB) cell lines.
PROCEDURE: In this study, we examined the expression of EPHB and EFNB transcripts in 24 NB specimens representing all clinical stages. We found that several EPHB and EFNB transcripts were expressed together in all NBs examined.
RESULTS: Among the transcripts examined, EPHB6 expression was most significantly associated with low stage tumors (stages 1, 2, and 4S; P = 0.0048). TrkA expression was significantly correlated with EPHB6, EFNB2, and EFNB3 expression (P < 0.01 in each case). Taken together, these data indicate that the expression of EPHB6, EFNB2, and EFNB3 may serve as prognostic indicators of favorable NBs. In the low-stage NBs without MYCN amplification, EPHB2 expression was correlated both with MYCN expression and with TrkA expression (P < 0.01 in each case). Moreover, MYCN expression was correlated with TrkA expression (P < 0.01) in the low-stage NBs.
CONCLUSIONS: This observation points to the possibility that MYCN expression might contribute to favorable outcome of low-stage NBs.

Tang XX, Zhao H, Robinson ME, et al.
Prognostic significance of EPHB6, EFNB2, and EFNB3 expressions in neuroblastoma.
Med Pediatr Oncol. 2000; 35(6):656-8 [PubMed] Related Publications
BACKGROUND: EPH family receptor tyrosine kinases and their ligand ephrins play pivotal roles in development. High-level expression of transcripts encoding EPHB6 receptors (EPHB6), its ligands ephrin-B2 and ephrin-B3 (EFNB2, EFNB3) is predictive of favorable disease outcome of neuroblastoma (NB). When combined with TrkA expression, the expression of EPHB6, EFNB2, or EFNB3 predicts more accurately the disease outcome than each of the four variables alone.
PROCEDURE: Cox regression and Kaplan-Meier analyses were used to assess the prognostic significance of EPHB6, EFNB2, EFNB3, and TrkA expressions in NB without MYCN amplification.
RESULTS: High-level expression of EFNB3 or TrkA predicted favorable NB outcome of NB without MYCN amplification (p < 0.03). As found in the general NB population, EPHB6, EFNB2, or EFNB3 expression in combination with TrkA expression was significantly predictive of the disease outcome of normal MYCN NB (p < 0.01).
CONCLUSIONS: EPHB6, EFNB2, and EFNB3 expressions may permit further refinement of the prognostic stratification of NB into favorable and unfavorable groups.

Tang XX, Zhao H, Robinson ME, et al.
Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma.
Proc Natl Acad Sci U S A. 2000; 97(20):10936-41 [PubMed] Free Access to Full Article Related Publications
Neuroblastoma (NB) is a common pediatric tumor that exhibits a wide range of biological and clinical heterogeneity. EPH (erythropoietin-producing hepatoma amplified sequence) family receptor tyrosine kinases and ligand ephrins play pivotal roles in neural and cardiovascular development. High-level expression of transcripts encoding EPHB6 receptors (EPHB6) and its ligands ephrin-B2 and ephrin-B3 (EFNB2, EFNB3) is associated with low-stage NB (stages 1, 2, and 4S) and high TrkA expression. In this study, we showed that EFNB2 and TrkA expressions were associated with both tumor stage and age, whereas EPHB6 and EFNB3 expressions were solely associated with tumor stage, suggesting that these genes were expressed in distinct subsets of NB. Kaplan-Meier and Cox regression analyses revealed that high-level expression of EPHB6, EFNB2, and EFNB3 predicted favorable NB outcome (P<0.005), and their expression combined with TrkA expression predicted the disease outcome more accurately than each variable alone (P<0.00005). Interestingly, if any one of the four genes (EPHB6, EFNB2, EFNB3, or TrkA) was expressed at high levels in NB, the patient survival was excellent (>90%). To address whether a good disease outcome of NB was a consequence of high-level expression of a "favorable NB gene," we examined the effect of EPHB6 on NB cell lines. Transfection of EPHB6 cDNA into IMR5 and SY5Y expressing little endogenous EPHB6 resulted in inhibition of their clonogenicity in culture. Furthermore, transfection of EPHB6 suppressed the tumorigenicity of SY5Y in a mouse xenograft model, demonstrating that high-level expressions of favorable NB genes, such as EPHB6, can in fact suppress malignant phenotype of unfavorable NB.

Tang XX, Evans AE, Zhao H, et al.
High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas.
Clin Cancer Res. 1999; 5(6):1491-6 [PubMed] Related Publications
Neuroblastoma (NB) is a common pediatric tumor of neural crest origin that is biologically and clinically heterogeneous. EPH family receptor tyrosine kinases and ephrin ligands play fundamental roles in neurodevelopmental processes. Recently, we found that NB cell lines expressed several EPHB and EFNB transcripts, which encode EPHB subgroup receptors and ephrin-B subgroup ligands, respectively. To explore the role of EPHB receptors and ephrin-B ligands in the biology of NB, we examined the expression of EPHB and EFNB transcripts in 47 primary NB specimens. Multiple EPHB and EFNB transcripts were expressed in all of the NB tumors examined, suggesting the involvement of these transcripts in modulating the biological behavior of NB. Higher levels of EPHB6, EFNB2, and EFNB3 expression were found in low-stage tumors (stage 1, 2, and 4S) than in advanced-stage tumors (stage 3 and 4; P = 0.0013, P = 0.0048, and P = 0.027, respectively). Expression of TrkA, a well-established prognostic marker of favorable NB, was positively correlated with EPHB6, EFNB2, and EFNB3 expression (P < 0.0001, P = 0.0019, and P = 0.0001, respectively). MYCN-amplified tumors expressed lower levels of EPHB6, EFNB2, EFNB3, and TrkA transcripts compared to nonamplified tumors (P = 0.0006, P = 0.0023, P = 0.0048, and P = 0.0001, respectively). These data suggest that high-level expression of EPHB6, EFNB2, and EFNB3 is associated with favorable NB and that low-level expression of EPHB6, EFNB2, and EFNB3 correlates with aggressive MYCN-amplified NB. Thus, EPHB6, EFNB2, and EFNB3 may have biological relevance in NB. Further investigation on the biology of these genes may help provide insight into the treatment of NB.

Tang XX, Brodeur GM, Campling BG, Ikegaki N
Coexpression of transcripts encoding EPHB receptor protein tyrosine kinases and their ephrin-B ligands in human small cell lung carcinoma.
Clin Cancer Res. 1999; 5(2):455-60 [PubMed] Related Publications
The EPH family is the largest subfamily of receptor protein tyrosine kinases, consisting of the EPHA and EPHB subgroups. Ephrin-B1, ephrin-B2, and ephrin-B3 are ligands of the EPHB subgroup and are encoded by the EFNB1, EFNB2, and EFNB3 genes, respectively. We have shown previously that EPHB2 transcripts are expressed in six small cell lung carcinoma (SCLC) cell lines. In this study, we examined the expression of EPHB1, EPHB2, EPHB3, EPHB4, and EPHB6 in 4 SCLC tumor specimens and 14 cell lines including 3 cell lines derived from these tumor specimens. To investigate whether potential autocrine loops of EPHB receptors and ephrin-B ligands exist in SCLC, the expression of EFNB1, EFNB2, and EFNB3 was also examined. Our data show that transcripts encoding multiple members of the EPHB subgroup and the ephrin-B subgroup are coexpressed in SCLC cell lines and tumors. These results suggest that the EPHB subgroup receptor kinases may modulate the biological behavior of SCLC through autocrine and/or juxtacrine activation by ephrin-B ligands that are expressed in the same or neighboring cells.

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