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1.
J Comp Neurol ; 526(16): 2706-2721, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30156295

RESUMEN

In the multimodal lateral cortex of the inferior colliculus (LCIC), there are two neurochemically and connectionally distinct compartments, termed modular and extramodular zones. Modular fields span LCIC layer 2 and are recipients of somatosensory afferents, while encompassing extramodular domains receive auditory inputs. Recently, in developing mice, we identified several markers (among them glutamic acid decarboxylase, GAD) that consistently label the same modular set, and a reliable extramodular marker, calretinin, (CR). Previous reports from our lab show similar modular-extramodular patterns for certain Eph-ephrin guidance members, although their precise alignment with the developing LCIC neurochemical framework has yet to be addressed. Here we confirm in the nascent LCIC complementary GAD/CR-positive compartments, and characterize the registry of EphA4 and ephrin-B2 expression patterns with respect to its emerging modular-extramodular organization. Immunocytochemical approaches in GAD67-GFP knock-in mice reveal patchy EphA4 and ephrin-B2 domains that precisely align with GAD-positive LCIC modules, and are complementary to CR-defined extramodular zones. Such patterning was detectable neonatally, yielding discrete compartments prior to hearing onset. A dense plexus of EphA4-positive fibers filled modules, surrounding labeled ephrin-B2 and GAD cell populations. The majority of observed GABAergic neurons within modular boundaries were also positive for ephrin-B2. These results suggest an early compartmentalization of the LCIC that is likely instructed in part through Eph-ephrin guidance mechanisms. The overlap of developing LCIC neurochemical and guidance patterns is discussed in the context of its seemingly segregated multimodal input-output streams.


Asunto(s)
Colículos Inferiores/crecimiento & desarrollo , Colículos Inferiores/metabolismo , Neurogénesis/fisiología , Neuronas/citología , Neuronas/metabolismo , Animales , Vías Auditivas/citología , Vías Auditivas/crecimiento & desarrollo , Vías Auditivas/metabolismo , Efrina-B2/análisis , Efrina-B2/biosíntesis , Femenino , Colículos Inferiores/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor EphA4/análisis , Receptor EphA4/biosíntesis
2.
Mol Cell Biochem ; 439(1-2): 95-104, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28795314

RESUMEN

MicroRNAs (miRNAs) are small noncoding RNAs that exert their functions by targeting specific mRNA sequences. Many studies have demonstrated that miRNAs are crucial for cancer progression, during which they can act as either oncogenes or tumor suppressors. Previous research has shown that miR-335 is downregulated in breast cancer, and it has been shown to be a breast cancer suppressor. In addition, emerging evidence indicates that erythropoietin-producing hepatocellular A4 (EphA4) is implicated in cancer cell proliferation, migration, and invasion. However, little is known about the relationship between miR-335 and EphA4 in breast cancer. In the present study, we used bioinformatic and biochemical analyses to demonstrate that EphA4 is a direct downstream target of miR-335 in human breast cancer MCF-7 and MDA-MB-23 cells and revealed that miR-335 negatively regulates the expression of EphA4 in these cells. Further investigation revealed that miR-335 overexpression inhibits MCF-7 and MDA-MB-231 cell proliferation and that this inhibition is attenuated by EphA4 coexpression. Similarly, miR-335 overexpression also inhibited growth and downregulated EphA4 expression in tumors in nude mice. Moreover, our results demonstrated that miR-335 overexpression suppresses migration and invasion in MCF-7 and MDA-MB-231 cells, an effect that was reversed by EphA4 overexpression. These findings confirmed that EphA4 is a direct target gene of miR-335 and that miR-335 suppresses breast cancer cell proliferation and motility in part by directly inhibiting EphA4 expression.


Asunto(s)
Neoplasias de la Mama/metabolismo , Movimiento Celular , Proliferación Celular , MicroARNs/metabolismo , Proteínas de Neoplasias/biosíntesis , ARN Neoplásico/metabolismo , Receptor EphA4/biosíntesis , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Células MCF-7 , Ratones , Ratones Desnudos , MicroARNs/genética , Invasividad Neoplásica , Proteínas de Neoplasias/genética , ARN Neoplásico/genética , Receptor EphA4/genética
3.
Tumour Biol ; 39(3): 1010428317694298, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28351297

RESUMEN

Eph receptor A4 (EphA4), a member of the erythropoietin-producing hepatocellular (Eph) family, has been reported to upregulate in several tumors. However, the role of EphA4 in multiple myeloma has not been clarified yet. In this study, we found that EphA4 promoted proliferation of multiple myeloma cells via the regulation of cell cycle. Besides, EphA4 was closely related to cell adhesion of multiple myeloma cells and promoted cell adhesion-mediated drug resistance by enhancing the phosphorylation levels of Akt (p-AKT) expression in multiple myeloma. More interestingly, we discovered that EphA4 can interact with cyclin-dependent kinase 5 (CDK5) and regulate its expression in multiple myeloma. CDK5 has been reported to be overexpressed in multiple myeloma which mediated bortezomib resistance and also participated in AKT pathway. And we have also proved the fact. So, we supposed that EphA4 interacted with CDK5 and promoted its expression which in turn enhanced p-AKT expression and promoted cell adhesion-mediated drug resistance in multiple myeloma. Therefore, this study clarifies the molecular mechanism of cell adhesion-mediated drug resistance and may be useful in identifying potential target for treatment of multiple myeloma.


Asunto(s)
Quinasa 5 Dependiente de la Ciclina/biosíntesis , Mieloma Múltiple/genética , Proteína Oncogénica v-akt/genética , Receptor EphA4/genética , Bortezomib/administración & dosificación , Adhesión Celular/genética , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 5 Dependiente de la Ciclina/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Mieloma Múltiple/patología , Proteína Oncogénica v-akt/biosíntesis , Fosforilación , Receptor EphA4/biosíntesis , Transducción de Señal/efectos de los fármacos
4.
Pathol Int ; 66(9): 506-10, 2016 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-27478038

RESUMEN

The expression of EphA4 has been well documented in the development of nerve and in certain types of human cancer. Few studies of EphA4, however, have focused on breast carcinoma. In this study, a set of breast carcinomas was subjected to immunohistochemical staining. In normal luminal cells, EphA4 was weakly detected in 11 (14.3 %), moderately detected in 15 (19.5 %) and highly detected in 51 out of 77 (66.2 %) samples, while in breast carcinoma cells, EphA4 was weakly detected in 42 (54.5 %), moderately detected in 19 (24.7 %) and highly detected in 16 out of 77 (20.8 %) samples (P < 0.001). The expression of EphA4 protein was significantly reduced in 68.8 % of breast carcinoma samples comparing with normal cells. The expression of EphA4 was significantly associated with tumor grade (P = 0.003), TNM stage (P = 0.034), lymph node metastasis (P = 0.034) and Ki-67 (P < 0.001). No significant relationship was found between the expression of EphA4 and age, molecular subtypes, and HER2 status. Survival analysis showed that significant association of low expression of EphA4 in tumor cells with short overall survival (P = 0.048) and disease-free survival (P = 0.051). Our data show that EphA4 was reduced in breast carcinoma, which is associated with high grade, advanced TNM stage, lymph node metastasis, and poor outcome of patients.


Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Receptor EphA4/biosíntesis , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Metástasis Linfática , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Receptor EphA4/análisis
5.
Tumour Biol ; 37(8): 11429-41, 2016 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-27002617

RESUMEN

Despite advances in the roles of long non-coding RNA (lncRNA) tumor suppressor candidate 7 (TUSC7) in cancer biology, which has been identified as a tumor suppressor by regulating cell proliferation, apoptosis, migration, invasion, cell cycle, and tumor growth, the function of TUSC7 in hepatocellular carcinoma (HCC) remains unknown. In this study, we observed that the expression of TUSC7 was immensely decreased in HCC. Clinically, the lower expression of TUSC7 predicted poorer survival and may be an independent risk factor for HCC patients. Moreover, TUSC7 inhibited cell metastasis, invasion, and epithelial-to-mesenchymal transformation (EMT) through competitively binding miR-10a. Furthermore, we found that TUSC7 could decrease the expression of Eph tyrosine kinase receptor A4 (EphA4), a downstream target of miR-10a as well as an EMT suppressor, through TUSC7-miR-10a-EphA4 axis. Taken together, we demonstrate that TUSC7 suppresses EMT through the TUSC7-miR-10a-EphA4 axis, which may be a potential target for therapeutic intervention in HCC.


Asunto(s)
Carcinoma Hepatocelular/patología , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Hepáticas/patología , MicroARNs/genética , ARN Largo no Codificante/genética , Adulto , Anciano , Western Blotting , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/mortalidad , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor EphA4/biosíntesis , Receptor EphA4/genética , Transfección
6.
Sleep ; 39(3): 613-24, 2016 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-26612390

RESUMEN

STUDY OBJECTIVES: Optimal sleep is ensured by the interaction of circadian and homeostatic processes. Although synaptic plasticity seems to contribute to both processes, the specific players involved are not well understood. The EphA4 tyrosine kinase receptor is a cell adhesion protein regulating synaptic plasticity. We investigated the role of EphA4 in sleep regulation using electrocorticography in mice lacking EphA4 and gene expression measurements. METHODS: EphA4 knockout (KO) mice, Clock(Δ19/Δ19) mutant mice and littermates, C57BL/6J and CD-1 mice, and Sprague-Dawley rats were studied under a 12 h light: 12 h dark cycle, under undisturbed conditions or 6 h sleep deprivation (SLD), and submitted to a 48 h electrophysiological recording and/or brain sampling at different time of day. RESULTS: EphA4 KO mice showed less rapid eye movement sleep (REMS), enhanced duration of individual bouts of wakefulness and nonrapid eye movement sleep (NREMS) during the light period, and a blunted daily rhythm of NREMS sigma activity. The NREMS delta activity response to SLD was unchanged in EphA4 KO mice. However, SLD increased EphA4 expression in the thalamic/hypothalamic region in C57BL/6J mice. We further show the presence of E-boxes in the promoter region of EphA4, a lower expression of EphA4 in Clock mutant mice, a rhythmic expression of EphA4 ligands in several brain areas, expression of EphA4 in the suprachiasmatic nuclei of the hypothalamus (SCN), and finally an unchanged number of cells expressing Vip, Grp and Avp in the SCN of EphA4 KO mice. CONCLUSIONS: Our results suggest that EphA4 is involved in circadian sleep regulation.


Asunto(s)
Ritmo Circadiano/fisiología , Receptor EphA4/metabolismo , Privación de Sueño/fisiopatología , Sueño/fisiología , Animales , Proteínas CLOCK/genética , Ritmo Circadiano/genética , Oscuridad , Electrocorticografía , Fenómenos Electrofisiológicos , Homeostasis , Luz , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Plasticidad Neuronal , Regiones Promotoras Genéticas/genética , Ratas , Ratas Sprague-Dawley , Receptor EphA4/biosíntesis , Receptor EphA4/deficiencia , Receptor EphA4/genética , Sueño/genética , Privación de Sueño/genética , Sueño REM/genética , Sueño REM/fisiología , Núcleo Supraquiasmático/metabolismo , Tálamo/metabolismo , Factores de Tiempo , Vigilia/genética , Vigilia/fisiología
7.
J Neuroimmune Pharmacol ; 8(1): 333-44, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23314923

RESUMEN

Despite the successes of combination antiretroviral therapy, HIV-associated neurocognitive disorders persist in many infected individuals. Earlier studies showed that neurocognitive impairment was associated with glutamate toxicity and synaptodendritic damage. We examined alterations in expression of four ephrin genes that are involved in synapse formation and recruitment of glutamate receptors to synapses, in the caudate and anterior cingulate in postmortem brain of cognitively characterized HIV-infected subjects, along with expression of neuronal and astroglial/macroglial markers. Postmortem tissues of HIV-infected and control subjects were obtained from the Manhattan HIV Brain Bank. HIV-infected subjects underwent neurocognitive assessment prior to death. Quantification of mRNA of genes of chemokine receptors and chemokines (CCR5, CXCR4, CCL2), astroglial/microglial markers (GFAP, CD163, CD68), the neuronal marker SNAP25, ephrin receptors EPHA4 and EPHB2, and ephrin ligands EFNB1 and EFNB2 was performed using SYBR Green RT-PCR. Proinflammatory chemokine and glial/macrophage mRNA levels in both regions were significantly greater in HIV+ than in HIV- subjects. Levels of EPHA4 and EFNB2 mRNA in the caudate, and EPHB2 mRNA in anterior cingulate were significantly lower in HIV+ subjects (p < 0.002, p < 0.02, p < 0.05, respectively). These transcripts also showed correlations with immune status and cognitive function within the HIV-infected group. Decreased levels of EFNB2 mRNA in the caudate correlated with lower CD4 counts (P < 0.05). Cognitive associations were limited to the cingulate, where decreased levels of EPHB2 mRNA were associated with better global cognitive status. Decreased cingulate expression of EPHB2 may represent a compensatory mechanism minimizing excitotoxic injury in the face of chronic inflammation.


Asunto(s)
Complejo SIDA Demencia/metabolismo , Química Encefálica/fisiología , Trastornos del Conocimiento/metabolismo , Infecciones por VIH/metabolismo , Receptores de la Familia Eph/biosíntesis , Adulto , Anciano , Núcleo Caudado/metabolismo , Función Ejecutiva , Femenino , Expresión Génica/efectos de los fármacos , Giro del Cíngulo/metabolismo , Humanos , Ligandos , Masculino , Persona de Mediana Edad , Peso Molecular , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor EphA4/biosíntesis , Receptores de la Familia Eph/genética , Bancos de Tejidos , Carga Viral , Adulto Joven
8.
Hepatology ; 57(2): 667-77, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22996586

RESUMEN

UNLABELLED: MicroRNAs (miRNAs) have been reported to be associated with the development of cancers. However, the function of miRNAs in human hepatocellular carcinoma (HCC) remains largely undefined. Here we found that overexpression of miR-10a promoted the migration and invasion of QGY-7703 and HepG2 cells in vitro but suppressed metastasis in vivo. Cell adhesion assays showed that miR-10a suppressed HCC cell-matrix adhesion, which could explain the results of the in vivo animal experiments. The Eph tyrosine kinase receptor, EphA4, was identified as the direct and functional target gene of miR-10a. Knockdown of EphA4 phenocopied the effect of miR-10a and ectopic expression of EphA4 restored the effect of miR-10a on migration, invasion, and adhesion in HCC cells. We further demonstrated that miR-10a and EphA4 regulated the epithelial-mesenchymal transition process and the ß1-integrin pathway to affect cell invasion and adhesion. CONCLUSION: Our findings highlight the importance of miR-10a in regulating the metastatic properties of HCC by directly targeting EphA4 and may provide new insights into the pathogenesis of HCC.


Asunto(s)
Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/secundario , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Neoplasias Hepáticas/patología , MicroARNs/fisiología , Metástasis de la Neoplasia/fisiopatología , Receptor EphA4/metabolismo , Línea Celular Tumoral , Uniones Célula-Matriz/metabolismo , Femenino , Células Hep G2 , Humanos , Hígado/metabolismo , Masculino , Invasividad Neoplásica , Receptor EphA4/biosíntesis
9.
Dev Neurobiol ; 71(2): 182-99, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20886601

RESUMEN

Central processing of complex auditory tasks requires elaborate circuitry. The auditory midbrain, or inferior colliculus (IC), epitomizes such precise organization, where converging inputs form discrete, tonotopically-arranged axonal layers. Previously in rat, we established that shaping of multiple afferent patterns in the IC central nucleus (CNIC) occurs prior to experience. This study implicates an Eph receptor tyrosine kinase and a corresponding ephrin ligand in signaling this early topographic registry. We report that EphA4 and ephrin-B2 expression patterns in the neonatal rat and mouse IC correlate temporally and spatially with that of developing axonal layers. DiI-labeling confirms projections arising from the lateral superior olive (LSO) form frequency-specific layers within the ipsilateral and contralateral mouse CNIC, as has been described in other species. Immunohistochemistry (EphA4 and ephrin-B2) and ephrin-B2 lacZ histochemistry reveal clear gradients in expression across the tonotopic axis, with most concentrated labeling observed in high-frequency, ventromedial aspects of the CNIC. Discrete patches of labeling were also discernible in the external cortex of the IC (ECIC; EphA4 patches in rat, ephrin-B2 patches in mouse). Observed gradients in the CNIC and compartmentalized ECIC expression persisted through the first postnatal week, before becoming less intense and more homogeneously distributed by the functional onset of hearing. EphA4 and ephrin-B2-positive neurons were evident in several auditory brainstem nuclei known to send patterened inputs to the IC. These findings suggest the involvement of cell-cell EphA4 and ephrin-B2 signaling in establishing order in the developing IC.


Asunto(s)
Vías Auditivas/metabolismo , Efrina-B2/biosíntesis , Colículos Inferiores/metabolismo , Neurogénesis/fisiología , Receptor EphA4/biosíntesis , Animales , Animales Recién Nacidos , Vías Auditivas/citología , Vías Auditivas/crecimiento & desarrollo , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Colículos Inferiores/citología , Colículos Inferiores/crecimiento & desarrollo , Ratones , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-Dawley , Transducción de Señal
10.
J Neurosci ; 30(47): 16015-24, 2010 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-21106840

RESUMEN

There is growing evidence that astrocytes play critical roles in neuron-glial interactions at the synapse. Astrocytes are believed to regulate presynaptic and postsynaptic structures and functions, in part, by the release of gliotransmitters such as glutamate, ATP, and d-serine; however, little is known of how neurons and astrocytes communicate to regulate these processes. Here, we investigated a family of transmembrane proteins called ephrinBs and Eph receptors that are expressed in the synapse and are known to regulate synaptic transmission and plasticity. In addition to their presence on CA1 hippocampal neurons, we determined that ephrins and Eph receptors are also expressed on hippocampal astrocytes. Stimulation of hippocampal astrocytes with soluble ephrinB3, known to be expressed on CA1 postsynaptic dendrites, enhanced d-serine synthesis and release in culture. Conversely, ephrinB3 had no effect on d-serine release from astrocytes deficient in EphB3 and EphA4, which are the primary receptors for ephrinB3. Eph receptors mediate this response through interactions with PICK1 (protein interacting with C-kinase) and by dephosphorylating protein kinase C α to activate the conversion of l-serine to d-serine by serine racemase. These findings are supported in vivo, where reduced d-serine levels and synaptic transmissions are observed in the absence of EphB3 and EphA4. These data support a role for ephrins and Eph receptors in regulating astrocyte gliotransmitters, which may have important implications on synaptic transmission and plasticity.


Asunto(s)
Astrocitos/metabolismo , Efrina-B3/fisiología , Serina/biosíntesis , Serina/metabolismo , Animales , Células Cultivadas , Efrina-B3/deficiencia , Hipocampo/metabolismo , Ratones , Ratones Noqueados , Ratones Transgénicos , Plasticidad Neuronal/genética , Biosíntesis de Proteínas/genética , Receptor EphA4/biosíntesis , Receptor EphA4/deficiencia , Receptor EphA4/fisiología , Serina/análogos & derivados , Estereoisomerismo , Transmisión Sináptica/genética
11.
J Neurotrauma ; 27(7): 1321-32, 2010 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-20486805

RESUMEN

Glial scar formation occurs in response to brain injury in mammalian models and inhibits axonal growth. Identification of molecules that may mediate reactivity of astrocytes has become a leading therapeutic goal in the field of neurotrauma. In adult rodent brain and spinal cord, many of the Eph receptors and their ephrin ligands have been demonstrated to be upregulated on reactive astrocytes at the injury site; however, little is known about the expression of these molecules in nonhuman primate injury models. This study examines the role of the tyrosine kinase EphA4 receptor, which predominantly binds most ephrin ligands, after injury in marmoset monkey brain. Following lesioning of the primary visual cortex (V1) in the adult marmoset, EphA4 is strongly upregulated on reactive astrocytes around the lesion site, which secrete extracellular matrix molecules such as chondroitin sulfate proteoglycans, which are known for their inhibitory effect on axonal growth and regeneration. This astrocyte reactivity was also associated with neuronal death in the area adjacent to the lesion site. EphA4 activation induced by clustered ephrin A5-Fc-mediated astrocyte proliferation and glial fibrillary acidic protein expression in vitro, as demonstrated by closure of scratched wound and MTT assays, occurs via two potential signaling pathways, the mitogen-activated protein kinase and Rho pathways. These results in a nonhuman primate model highlight the importance of developing pharmacotherapeutic approaches to block these molecules following brain injury.


Asunto(s)
Astrocitos/metabolismo , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/patología , Corteza Cerebral/metabolismo , Gliosis/metabolismo , Gliosis/patología , Receptor EphA4/biosíntesis , Regulación hacia Arriba/fisiología , Animales , Astrocitos/patología , Biomarcadores/metabolismo , Lesiones Encefálicas/complicaciones , Callithrix , Muerte Celular/fisiología , Corteza Cerebral/lesiones , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Efrina-A5/metabolismo , Efrinas/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/etiología , Receptor EphA4/fisiología
12.
Pathol Oncol Res ; 16(2): 267-76, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-19949912

RESUMEN

Ephrin (Eph) receptors have been reported to be frequently overexpressed in a wide variety of cancer types, being associated with tumor growth, invasion, metastasis and angiogenesis. The aim of the present study was to evaluate the clinical significance of Eph-A1, -A2, -A4, -A5 and -A7 expression in pancreatic ductal adenocarcinoma. Eph-A1, -A2, -A4, -A5 and -A7 expression and staining intensity were assessed immunohistochemically in tumoral samples of 67 pancreatic adenocarcinoma patients and were statistically analyzed in relation to clinicopathological characteristics, tumor proliferative capacity and patients' survival. Eph receptors were abundantly expressed in pancreatic ductal adenocarcinoma cases examined. Eph-A1 staining intensity was significantly associated with tumor size (pT, p = 0.008) and tumor histopathological stage (pStage, p = 0.012). Eph-A2 expression was significantly associated with patients' age (p = 0.007), while Eph-A4 and Eph-A5 with tumor proliferative capacity (p = 0.019 and p = 0.011, respectively). Pancreatic adenocarcinoma patients with moderate/intense Eph-A5 or Eph-A7 staining presented significantly shorter survival times compared to those with negative/mild one (log-rank test, p = 0.024 and p = 0.009, respectively). Multivariate analysis identified Eph-A5 and Eph-A7 staining intensity as independent prognostic factors (p = 0.048 and p = 0.004, respectively). In conclusion, the present study revealed that Eph receptors were associated with pancreatic cancer characteristics, supporting evidence for their potential clinical application in management and prognosis of pancreatic adenocarcinoma patients.


Asunto(s)
Biomarcadores de Tumor/análisis , Carcinoma Ductal Pancreático/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores de la Familia Eph/biosíntesis , Anciano , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Estadificación de Neoplasias , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Receptor EphA1/biosíntesis , Receptor EphA2/biosíntesis , Receptor EphA4/biosíntesis , Receptor EphA5/biosíntesis , Receptor EphA7/biosíntesis
13.
Int J Oncol ; 33(3): 573-7, 2008 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-18695888

RESUMEN

The Eph receptors, members of a large family of transmembrane receptor tyrosine kinases, play important roles in a variety of biological functions. Recent studies have suggested that EphA4 and EphB2 participate in the growth and development of various carcinomas. This study examined the relationship of EphA4 and EphB2 gene expression to clinicopathological factors, especially metastasis, in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 205 patients with untreated colorectal cancer. The relative expression levels of EphA4 and EphB2 mRNA in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. The relative expression level of EphA4 mRNA was higher in the presence than in the absence of liver metastasis, whereas the relative expression levels of EphB2 mRNA were similar. Analysis of the relationship between clinicopathological features and gene expression showed that high expression of the EphA4 gene and low expression of the EphB2 gene correlated with liver metastasis. There was no correlation between EphA4 and EphB2 gene expression. Our results suggest that overexpression of the EphA4 gene and reduced expression of the EphB2 gene might promote liver metastasis in colorectal cancer. Overexpression of the EphA4 gene and reduced expression of the EphB2 gene may thus be a useful predictor of liver metastasis in patients with colorectal cancer.


Asunto(s)
Adenocarcinoma/secundario , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/secundario , Receptor EphA4/biosíntesis , Receptor EphB2/biosíntesis , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Anciano , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Expresión Génica , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Masculino , ARN Mensajero/análisis , Receptor EphA4/genética , Receptor EphB2/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
14.
Neurosci Lett ; 418(1): 49-54, 2007 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-17418490

RESUMEN

Spinal cord injury (SCI) causes an increase of inhibitory factors that may restrict axonal outgrowth after trauma. During the past decade, the Eph receptors and ephrin ligands have emerged as key repulsive cues known to be involved in neurite outgrowth, synapse formation, and axonal pathfinding during development. Given the non-permissive environment for axonal regeneration after SCI, we questioned whether enhanced-expression of the EphA4 receptor with repulsive activity for axonal outgrowth is potentially responsible for the regenerative failure. To address this possibility, we have examined the expression of EphA4 after SCI in adult rats following a contusion SCI. EphA4 expression studies demonstrated a time-dependent change for EphA4 protein without alterations in beta-actin. EphA4 was downregulated initially and upregulated 7 days after injury. Blockade of EphA4 upregulation with antisense oligonucleotides did not produce an anatomical or physiological response monitored with anterograde tracing studies or transcranial magnetic motor evoked potentials (tcMMEP), respectively. These results demonstrated that upregulation of EphA4 receptors after trauma is not related to axonal regeneration or return of nerve conduction across the injury site.


Asunto(s)
Potenciales Evocados Motores/fisiología , Regeneración Nerviosa/fisiología , Receptor EphA4/biosíntesis , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/patología , Animales , Axones/fisiología , Western Blotting , Femenino , Ratas , Ratas Sprague-Dawley , Estimulación Magnética Transcraneal
15.
Development ; 132(22): 4937-50, 2005 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-16221730

RESUMEN

The neural crest is a multipotent, migratory cell population that contributes to a variety of tissues and organs during vertebrate embryogenesis. Here, we focus on the function of Msx1 and Msx2, homeobox genes implicated in several disorders affecting craniofacial development in humans. We show that Msx1/2 mutants exhibit profound deficiencies in the development of structures derived from the cranial and cardiac neural crest. These include hypoplastic and mispatterned cranial ganglia, dysmorphogenesis of pharyngeal arch derivatives and abnormal organization of conotruncal structures in the developing heart. The expression of the neural crest markers Ap-2alpha, Sox10 and cadherin 6 (cdh6) in Msx1/2 mutants revealed an apparent retardation in the migration of subpopulations of preotic and postotic neural crest cells, and a disorganization of neural crest cells paralleling patterning defects in cranial nerves. In addition, normally distinct subpopulations of migrating crest underwent mixing. The expression of the hindbrain markers Krox20 and Epha4 was altered in Msx1/2 mutants, suggesting that defects in neural crest populations may result, in part, from defects in rhombomere identity. Msx1/2 mutants also exhibited increased Bmp4 expression in migratory cranial neural crest and pharyngeal arches. Finally, proliferation of neural crest-derived mesenchyme was unchanged, but the number of apoptotic cells was increased substantially in neural crest-derived cells that contribute to the cranial ganglia and the first pharyngeal arch. This increase in apoptosis may contribute to the mispatterning of the cranial ganglia and the hypoplasia of the first arch.


Asunto(s)
Tipificación del Cuerpo/genética , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Factor de Transcripción MSX1/deficiencia , Factor de Transcripción MSX1/genética , Cresta Neural/embriología , Animales , Proteína Morfogenética Ósea 4 , Proteínas Morfogenéticas Óseas/metabolismo , Anomalías Cardiovasculares/genética , Movimiento Celular/genética , Cruzamientos Genéticos , Proteínas de Unión al ADN/fisiología , Proteína 2 de la Respuesta de Crecimiento Precoz/biosíntesis , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteínas de Homeodominio/biosíntesis , Proteínas de Homeodominio/fisiología , Factor de Transcripción MSX1/fisiología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Defectos del Tubo Neural/embriología , Defectos del Tubo Neural/genética , Receptor EphA4/biosíntesis , Receptor EphA4/genética , Rombencéfalo/embriología , Rombencéfalo/metabolismo , Cráneo/anomalías , Cráneo/embriología , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética
16.
J Neurosci ; 24(45): 10064-73, 2004 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-15537875

RESUMEN

Spinal cord injury usually results in permanent paralysis because of lack of regrowth of damaged neurons. Here we demonstrate that adult mice lacking EphA4 (-/-), a molecule essential for correct guidance of spinal cord axons during development, exhibit axonal regeneration and functional recovery after spinal cord hemisection. Anterograde and retrograde tracing showed that axons from multiple pathways, including corticospinal and rubrospinal tracts, crossed the lesion site. EphA4-/- mice recovered stride length, the ability to walk on and climb a grid, and the ability to grasp with the affected hindpaw within 1-3 months of injury. EphA4 expression was upregulated on astrocytes at the lesion site in wild-type mice, whereas astrocytic gliosis and the glial scar were greatly reduced in lesioned EphA4-/- spinal cords. EphA4-/- astrocytes failed to respond to the inflammatory cytokines, interferon-gamma or leukemia inhibitory factor, in vitro. Neurons grown on wild-type astrocytes extended shorter neurites than on EphA4-/- astrocytes, but longer neurites when the astrocyte EphA4 was blocked by monomeric EphrinA5-Fc. Thus, EphA4 regulates two important features of spinal cord injury, axonal inhibition, and astrocytic gliosis.


Asunto(s)
Astrocitos/patología , Axones/fisiología , Gliosis/genética , Regeneración Nerviosa/fisiología , Receptor EphA4/fisiología , Traumatismos de la Médula Espinal/fisiopatología , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Encéfalo/patología , División Celular/efectos de los fármacos , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Activación Enzimática , Fragmentos Fc de Inmunoglobulinas/farmacología , Interferón gamma/farmacología , Interleucina-6/farmacología , Cojera Animal/etiología , Cojera Animal/fisiopatología , Factor Inhibidor de Leucemia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuritas/ultraestructura , Paraplejía/etiología , Paraplejía/fisiopatología , Tractos Piramidales/patología , Receptor EphA4/biosíntesis , Receptor EphA4/deficiencia , Receptor EphA4/genética , Recuperación de la Función , Núcleo Rojo/patología , Traumatismos de la Médula Espinal/patología , Proteínas de Unión al GTP rho/metabolismo
17.
Cancer Res ; 64(17): 5963-72, 2004 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-15342375

RESUMEN

To characterize the molecular feature in prostate carcinogenesis and the putative transition from prostatic intraepithelial neoplasia (PIN) to invasive prostate cancer (PC), we analyzed gene-expression profiles of 20 PCs and 10 high-grade PINs with a cDNA microarray representing 23,040 genes. Considering the histological heterogeneity of PCs and the minimal nature of PIN lesions, we applied laser microbeam microdissection to purify populations of PC and PIN cells, and then compared their expression profiles with those of corresponding normal prostatic epithelium also purified by laser microbeam microdissection. A hierarchical clustering analysis separated the PC group from the PIN group, except for three tumors that were morphologically defined as one very-high-grade PIN and two low-grade PCs, suggesting that PINs and PCs share some molecular features and supporting the hypothesis of PIN-to-PC transition. On the basis of this hypothesis, we identified 21 up-regulated genes and 63 down-regulated genes commonly in PINs and PCs compared with normal epithelium, which were considered to be involved in the presumably early stage of prostatic carcinogenesis. They included AMACR, OR51E2, RODH, and SMS. Furthermore, we identified 41 up-regulated genes and 98 down-regulated genes in the transition from PINs to PCs; those altered genes, such as POV1, CDKN2C, EPHA4, APOD, FASN, ITGB2, LAMB2, PLAU, and TIMP1, included elements that are likely to be involved in cell adhesion or the motility of invasive PC cells. The down-regulation of EPHA4 by small interfering RNA in PC cells lead to attenuation of PC cell viability. These data provide clues to the molecular mechanisms underlying prostatic carcinogenesis, and suggest candidate genes the products of which might serve as molecular targets for the prevention and treatment of PC.


Asunto(s)
Transformación Celular Neoplásica/genética , Neoplasia Intraepitelial Prostática/genética , Neoplasia Intraepitelial Prostática/patología , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , División Celular/genética , Transformación Celular Neoplásica/patología , Análisis por Conglomerados , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Interferente Pequeño/genética , Receptor EphA4/antagonistas & inhibidores , Receptor EphA4/biosíntesis , Receptor EphA4/genética
18.
Cancer Res ; 64(16): 5578-86, 2004 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-15313894

RESUMEN

Sézary syndrome (Sz) is a malignancy of CD4+ memory skin-homing T cells and presents with erythroderma, lymphadenopathy, and peripheral blood involvement. To gain more insight into the molecular features of Sz, oligonucleotide array analysis was performed comparing gene expression patterns of CD4+ T cells from peripheral blood of patients with Sz with those of patients with erythroderma secondary to dermatitis and healthy controls. Using unsupervised hierarchical clustering gene, expression patterns of T cells from patients with Sz were classified separately from those of benign T cells. One hundred twenty-three genes were identified as significantly differentially expressed and had an average fold change exceeding 2. T cells from patients with Sz demonstrated decreased expression of the following hematopoietic malignancy-linked tumor suppressor genes: TGF-beta receptor II, Mxi1, Riz1, CREB-binding protein, BCL11a, STAT4, and Forkhead Box O1A. Moreover, the tyrosine kinase receptor EphA4 and the potentially oncogenic transcription factor Twist were highly and selectively expressed in T cells of patients with Sz. High expression of EphA4 and Twist was also observed in lesional skin biopsy specimens of a subset of patients with cutaneous T cell lymphomas related to Sz, whereas their expression was nearly undetectable in benign T cells or in skin lesions of patients with inflammatory dermatoses. Detection of EphA4 and Twist may be used in the molecular diagnosis of Sz and related cutaneous T-cell lymphomas. Furthermore, the membrane-bound EphA4 receptor may serve as a target for directed therapeutic intervention.


Asunto(s)
Proteínas Nucleares/biosíntesis , Receptor EphA4/biosíntesis , Síndrome de Sézary/genética , Neoplasias Cutáneas/genética , Factores de Transcripción/biosíntesis , Femenino , Perfilación de la Expresión Génica , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Receptor EphA4/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Síndrome de Sézary/enzimología , Síndrome de Sézary/metabolismo , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/metabolismo , Linfocitos T/enzimología , Linfocitos T/metabolismo , Linfocitos T/fisiología , Factores de Transcripción/genética , Proteína 1 Relacionada con Twist
19.
Mol Biol Cell ; 15(4): 1647-55, 2004 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-14742708

RESUMEN

The Eph family of receptor tyrosine kinases regulates numerous biological processes. To examine the biochemical and developmental contributions of specific structural motifs within Eph receptors, wild-type or mutant forms of the EphA4 receptor were ectopically expressed in developing Xenopus embryos. Wild-type EphA4 and a mutant lacking both the SAM domain and PDZ binding motif were constitutively tyrosine phosphorylated in vivo and catalytically active in vitro. EphA4 induced loss of cell adhesion, ventro-lateral protrusions, and severely expanded posterior structures in Xenopus embryos. Moreover, mutation of a conserved SAM domain tyrosine to phenylalanine (Y928F) enhanced the ability of EphA4 to induce these phenotypes, suggesting that the SAM domain may negatively regulate some aspects of EphA4 activity in Xenopus. Analysis of double mutants revealed that the Y928F EphA4 phenotypes were dependent on kinase activity; juxtamembrane sites of tyrosine phosphorylation and SH2 domain-binding were required for cell dissociation, but not for posterior protrusions. The induction of protrusions and expansion of posterior structures is similar to phenotypic effects observed in Xenopus embryos expressing activated FGFR1. Furthermore, the budding ectopic protrusions induced by EphA4 express FGF-8, FGFR1, and FGFR4a. In addition, antisense morpholino oligonucleotide-mediated loss of FGF-8 expression in vivo substantially reduced the phenotypic effects in EphA4Y928F expressing embryos, suggesting a connection between Eph and FGF signaling.


Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Receptor EphA4/fisiología , Secuencias de Aminoácidos , Animales , Western Blotting , Catálisis , Adhesión Celular , Membrana Celular/metabolismo , Clonación Molecular , Factor 8 de Crecimiento de Fibroblastos , Hibridación in Situ , Ratones , Mutación , Fenotipo , Fosforilación , Pruebas de Precipitina , Unión Proteica , Estructura Terciaria de Proteína , ARN/química , ARN/metabolismo , ARN Mensajero/metabolismo , Receptor EphA4/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Tirosina/química , Xenopus , Dominios Homologos src
20.
Neuron ; 39(3): 453-65, 2003 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-12895420

RESUMEN

The mechanisms generating precise connections between specific thalamic nuclei and cortical areas remain poorly understood. Using axon tracing analysis of ephrin/Eph mutant mice, we provide in vivo evidence that Eph receptors in the thalamus and ephrins in the cortex control intra-areal topographic mapping of thalamocortical (TC) axons. In addition, we show that the same ephrin/Eph genes unexpectedly control the inter-areal specificity of TC projections through the early topographic sorting of TC axons in an intermediate target, the ventral telencephalon. Our results constitute the first identification of guidance cues involved in inter-areal specificity of TC projections and demonstrate that the same set of mapping labels is used differentially for the generation of topographic specificity of TC projections between and within individual cortical areas.


Asunto(s)
Corteza Cerebral/metabolismo , Efrina-A4/genética , Efrina-A5/genética , Receptor EphA4/genética , Receptor EphA5/genética , Tálamo/metabolismo , Animales , Mapeo Encefálico/métodos , Corteza Cerebral/embriología , Corteza Cerebral/enzimología , Efrina-A4/biosíntesis , Efrina-A4/fisiología , Efrina-A5/biosíntesis , Efrina-A5/fisiología , Femenino , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Vías Nerviosas/embriología , Vías Nerviosas/enzimología , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Receptor EphA4/biosíntesis , Receptor EphA4/fisiología , Receptor EphA5/biosíntesis , Receptor EphA5/fisiología , Tálamo/embriología , Tálamo/enzimología
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