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Introduction: Dengue is an arboviral disease causing severe illness in over 500,000 people each year. Currently, there is no way to constrain dengue in the clinic. Host kinase regulators of dengue virus (DENV) infection have the potential to be disrupted by existing therapeutics to prevent infection and/or disease progression. Methods: To evaluate kinase regulation of DENV infection, we performed kinase regression (KiR), a machine learning approach that predicts kinase regulators of infection using existing drug-target information and a small drug screen. We infected hepatocytes with DENV in vitro in the presence of a panel of 38 kinase inhibitors then quantified the effect of each inhibitor on infection rate. We employed elastic net regularization on these data to obtain predictions of which of 291 kinases are regulating DENV infection. Results: Thirty-six kinases were predicted to have a functional role. Intriguingly, seven of the predicted kinases - EPH receptor A4 (EPHA4), EPH receptor B3 (EPHB3), EPH receptor B4 (EPHB4), erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 2 (FGFR2), Insulin like growth factor 1 receptor (IGF1R), and ret proto-oncogene (RET) - belong to the receptor tyrosine kinase (RTK) family, which are already therapeutic targets in the clinic. We demonstrate that predicted RTKs are expressed at higher levels in DENV infected cells. Knockdown of EPHB4, ERBB2, FGFR2, or IGF1R reduces DENV infection in hepatocytes. Finally, we observe differential temporal induction of ERBB2 and IGF1R following DENV infection, highlighting their unique roles in regulating DENV. Discussion: Collectively, our findings underscore the significance of multiple RTKs in DENV infection and advocate further exploration of RTK-oriented interventions against dengue.
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Virus del Dengue , Dengue , Humanos , Virus del Dengue/fisiología , Receptor EphA1 , Hepatocitos/metabolismo , Tirosina , Replicación ViralRESUMEN
INTRODUCTION: Genome-wide association studies link susceptibility to late-onset Alzheimer's disease (LOAD) with EphA1. Sequencing identified a non-synonymous substitution P460L as a LOAD risk variant. Other Ephs regulate vascular permeability and immune cell recruitment. We hypothesized that P460L dysregulates EphA1 receptor activity and impacts neuroinflammation. METHODS: EphA1/P460L receptor activity was assayed in isogenic Human Embryonic Kidney (HEK) cells. Soluble EphA1/P460L (sEphA1/sP460L) reverse signaling in brain endothelial cells was assessed by T-cell recruitment and barrier function assays. RESULTS: EphA1 and P460L were expressed in HEK cells, but membrane and soluble P460L were significantly reduced. Ligand engagement induced Y781 phosphorylation of EphA1 but not P460L. sEphA1 primed brain endothelial cells for increased T-cell recruitment; however, sP460L was less effective. sEphA1 decreased the integrity of the brain endothelial barrier, while sP460L had no effect. DISCUSSION: These findings suggest that P460L alters EphA1-dependent forward and reverse signaling, which may impact blood-brain barrier function in LOAD. HIGHLIGHTS: EphA1-dependent reverse signaling controls recruitment of T cells by brain endothelial cells. EphA1-dependent reverse signaling remodels brain endothelial cell contacts. LOAD-associated P460L variant of EphA1 shows reduced membrane expression and reduced ligand responses. LOAD-associated P460L variant of EphA1 fails to reverse signal to brain endothelial cells.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Barrera Hematoencefálica , Células Endoteliales , Estudio de Asociación del Genoma Completo , Ligandos , Receptor EphA1/metabolismoRESUMEN
Eph receptors and their Eph receptor-interacting (ephrin) ligands comprise a vital cell communication system with several functions. In cancer cells, there was evidence of bilateral Eph receptor signaling with both tumor-suppressing and tumor-promoting actions. As a member of the Eph receptor family, EphB4 has been linked to tumor angiogenesis, growth, and metastasis, which makes it a viable and desirable target for drug development in therapeutic applications. Many investigations have been conducted over the last decade to elucidate the structure and function of EphB4 in association with its ligand ephrinB2 for its involvement in tumorigenesis. Although several EphB4-targeting drugs have been investigated, and some selective inhibitors have been evaluated in clinical trials. This article addresses the structure and function of the EphB4 receptor, analyses its possibility as an anticancer therapeutic target, and summarises knowledge of EphB4 kinase inhibitors. To summarise, EphB4 is a difficult but potential treatment option for cancers.
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Neoplasias , Receptor EphA1 , Humanos , Efrina-B2/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Receptores de la Familia Eph , Receptor EphB4/genética , Receptor EphB4/metabolismoRESUMEN
Evidence implicating Eph receptor tyrosine kinases and their ephrin ligands (that together make up the 'Eph system') in cancer development and progression has been accumulating since the discovery of the first Eph receptor approximately 35 years ago. Advances in the past decade and a half have considerably increased the understanding of Eph receptor-ephrin signalling mechanisms in cancer and have uncovered intriguing new roles in cancer progression and drug resistance. This Review focuses mainly on these more recent developments. I provide an update on the different mechanisms of Eph receptor-ephrin-mediated cell-cell communication and cell autonomous signalling, as well as on the interplay of the Eph system with other signalling systems. I further discuss recent advances in elucidating how the Eph system controls tumour expansion, invasiveness and metastasis, supports cancer stem cells, and drives therapy resistance. In addition to functioning within cancer cells, the Eph system also mediates the reciprocal communication between cancer cells and cells of the tumour microenvironment. The involvement of the Eph system in tumour angiogenesis is well established, but recent findings also demonstrate roles in immune cells, cancer-associated fibroblasts and the extracellular matrix. Lastly, I discuss strategies under evaluation for therapeutic targeting of Eph receptors-ephrins in cancer and conclude with an outlook on promising future research directions.
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Neoplasias , Receptores de la Familia Eph , Humanos , Receptor EphA1 , Efrinas/fisiología , Efrinas/uso terapéutico , Neoplasias/patología , Procesos Neoplásicos , Microambiente TumoralRESUMEN
The Eph (erythropoietin-producing human hepatocellular) receptor family, the largest subclass of receptor tyrosine kinases (RTKs), plays essential roles in embryonic development and neurogenesis. The intracellular Sterile Alpha Motif (SAM) domain presents a critical structural feature that distinguishes Eph receptors from other RTKs and participates in recruiting and binding downstream molecules. This study identified SASH1 (SAM and SH3 domain containing 1) as a novel Eph receptor-binding partner through SAM-SAM domain interactions. Our comprehensive biochemical analyses revealed that SASH1 selectively interacts with Eph receptors via its SAM1 domain, displaying the highest affinity for EphA8. The high-resolution crystal structure of the EphA8-SASH1 complex provided insights into the specific intermolecular interactions between these proteins. Cellular assays confirmed that EphA8 and SASH1 co-localize and co-precipitate in mammalian cells, with cancer mutations (EphA8 R942H or G978D) impairing this interaction. We demonstrated that SAM-SAM interaction is critical for SASH1-mediated regulation of EphA8 kinase activity, shedding new light on the Eph signaling pathway and expanding our understanding of the molecular basis of the tumor suppressor gene SASH1.
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Receptor EphA1 , Motivo alfa Estéril , Proteínas Supresoras de Tumor , Animales , Femenino , Humanos , Embarazo , Desarrollo Embrionario , Receptor EphA1/genética , Receptores de la Familia Eph/genética , Transducción de SeñalRESUMEN
Chronic pain is a common and debilitating condition with a huge social and economic burden worldwide. Currently, available drugs in clinics are not adequately effective and possess a variety of severe side effects leading to treatment withdrawal and poor quality of life. The ongoing search for new therapeutics with minimal side effects for chronic pain management remains a high research priority. Erythropoietin-producing human hepatocellular carcinoma cell receptor (Eph) is a tyrosine kinase receptor that is involved in neurodegenerative disorders, including pain. The Eph receptor interacts with several molecular switches, such as N methyl d-aspartate receptor (NMDAR), mitogen-activated protein kinase (MAPK), calpain 1, caspase 3, protein kinase a (PKA), and protein kinase Cy (PKCy), which in turn regulates pathophysiology of chronic pain. Here we highlight the emerging evidence of the Ephs/ephrin system as a possible near-future therapeutic target for the treatment of chronic pain and discuss the various mechanism of its involvement. We critically analyse the present status of Eph receptor system and conclude that extrapolating the pharmacological and genetic approaches using a strong therapeutic development framework could serve as next-generation analgesics for the management of chronic pain.
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Dolor Crónico , Efrinas , Humanos , Efrinas/metabolismo , Receptor EphA1/metabolismo , Dolor Crónico/tratamiento farmacológico , Calidad de Vida , Transducción de SeñalRESUMEN
Deficiencies in epithelial barrier integrity are involved in the pathogenesis of chronic rhinosinusitis (CRS). This study aimed to investigate the role of ephrinA1/ephA2 signaling on sinonasal epithelial permeability and rhinovirus-induced epithelial permeability. This role in the process of epithelial permeability was evaluated by stimulating ephA2 with ephrinA1 and inactivating ephA2 with ephA2 siRNA or inhibitor in cells exposed to rhinovirus infection. EphrinA1 treatment increased epithelial permeability, which was associated with decreased expression of ZO-1, ZO-2, and occludin. These effects of ephrinA1 were attenuated by blocking the action of ephA2 with ephA2 siRNA or inhibitor. Furthermore, rhinovirus infection upregulated the expression levels of ephrinA1 and ephA2, increasing epithelial permeability, which was suppressed in ephA2-deficient cells. These results suggest a novel role of ephrinA1/ephA2 signaling in epithelial barrier integrity in the sinonasal epithelium, suggesting their participation in rhinovirus-induced epithelial dysfunction.
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Permeabilidad de la Membrana Celular , Células Epiteliales , Receptor EphA1 , Receptor EphA2 , Humanos , Permeabilidad de la Membrana Celular/genética , Permeabilidad de la Membrana Celular/fisiología , Células Epiteliales/metabolismo , Células Epiteliales/fisiología , Infecciones por Picornaviridae/metabolismo , Receptor EphA2/metabolismo , Rhinovirus/patogenicidad , ARN Bicatenario , ARN Interferente Pequeño/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Platelets play a crucial role in cancer and thrombosis. However, the receptor-ligand repertoire mediating prostate cancer (PCa) cell-platelet interactions and ensuing consequences have not been fully elucidated. Microvilli emanating from the plasma membrane of PCa cell lines (RC77 T/E, MDA PCa 2b) directly contacted individual platelets and platelet aggregates. PCa cell-platelet interactions were associated with calcium mobilization in platelets, and translocation of P-selectin and integrin αIIbß3 onto the platelet surface. PCa cell-platelet interactions reciprocally promoted PCa cell invasion and apoptotic resistance, and these events were insensitive to androgen receptor blockade by bicalutamide. PCa cells were exceedingly sensitive to activation by platelets in vitro, occurring at a PCa cell:platelet coculture ratio as low as 1:10 (whereas PCa patient blood contains 1:2,000,000 per ml). Conditioned medium from cocultures stimulated PCa cell invasion but not apoptotic resistance nor platelet aggregation. Candidate transmembrane signaling proteins responsible for PCa cell-platelet oncogenic events were identified by RNA-Seq and broadly divided into 4 major categories: (1) integrin-ligand, (2) EPH receptor-ephrin, (3) immune checkpoint receptor-ligand, and (4) miscellaneous receptor-ligand interactions. Based on antibody neutralization and small molecule inhibitor assays, PCa cell-stimulated calcium mobilization in platelets was found to be mediated by a fibronectin1 (FN1)-αIIbß3 signaling axis. Platelet-stimulated PCa cell invasion was facilitated by a CD55-adhesion G protein coupled receptor E5 (ADGRE5) axis, with contribution from platelet cytokines CCL3L1 and IL32. Platelet-stimulated PCa cell apoptotic resistance relied on ephrin-EPH receptor and lysophosphatidic acid (LPA)-LPA receptor (LPAR) signaling. Of participating signaling partners, FN1 and LPAR3 overexpression was observed in PCa specimens compared to normal prostate, while high expression of CCR1 (CCL3L1 receptor), EPHA1 and LPAR5 in PCa was associated with poor patient survival. These findings emphasize that non-overlapping receptor-ligand pairs participate in oncogenesis and thrombosis, highlighting the complexity of any contemplated clinical intervention strategy.
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Calcio , Neoplasias de la Próstata , Masculino , Humanos , Ligandos , Receptor EphA1 , IntegrinasRESUMEN
BACKGROUND: Eph receptors tyrosine kinase (RTK) were identified in 1987 from hepatocellular carcinoma cell lines and were the largest known subfamily of RTK. Eph receptors can be divided into two categories, EphA and EphB, based on their structure and receptor-ligand specificity. EphA can be divided into 10 species (EphA 1-10) and EphB into 6 species (EphB1-6). Similarly, the ligands of Eph receptors are Ephrins. Ephrins also can be divided into Ephrin A and Ephrin B, of which there are five species(Ephrin-A1-5) and three species(Ephrin-B1-3). Among the Eph receptors, EphA1 has been the least studied so far. As far as we know, Eph receptors are involved in multiple pathologies, including cancer progression, tumor angiogenesis, intestinal environmental stability, the lymph node system, neurological disease, and inhibition of nerve regeneration after injury. There is a link between EphA1, integrin and ECM- related signal pathways. Ephrin-A1 is a ligand of the EphA1 receptor. EphA1 and ephrin-A1 functions are related to tumor angiogenesis. EphA1 and ephrin-A1 also play roles in gynecological diseases. Ephrin-A1 and EphA1 receptors regulate the follicular formation, ovulation, embryo transport, implantation and placental formation, which are of great significance for the occurrence of gynecological tumor diseases. EphA1 has been identified as an oncoprotein in various tumors and has been associated with the prognosis of various tumors in recent years. EphA1 is considered a driver gene in tumor genomics. There are significant differences in EphA1 expression levels in different types of normal tissues and tumors and even in different stages of tumor development, suggesting its functional diversity. Changes at the gene level in cell biology are often used as biological indicators of cancer, known as biomarkers, which can be used to provide diagnostic or prognostic information and are valuable for improving the detection, monitoring and treatment of tumors. However, few prognostic markers can selectively predict clinically significant tumors with poor prognosis. These malignancies are more likely to progress and lead to death, requiring more aggressive treatment. Currently available treatments for advanced cancer are often ineffective, and treatment options are mainly palliative. Therefore, early identification and treatment of those at risk of developing malignant tumors are crucial. Although pieces of evidence have shown the role of EphA1 in tumorigenesis and development, its specific mechanism is still unknown to a great extent. OBJECTIVE: This review reveals the changes and roles of EphA1 in many tumors and cancers. The change of EphA1 expression can be used as a biological marker of cancer, which is valuable for improving tumor detection, monitoring and treatment and can be applied to imaging. Studies have shown that structural modification of EphA1 could make it an effective new drug. EphA1 is unique in that it can be considered a prognostic marker in many tumors and is of important meaning for clinical diagnosis and operative treatment. At the same time, the study of the specific mechanism of EphA1 in tumors can provide a new way for targeted therapy. METHODS: Relevant studies were retrieved and collected through the PubMed system. After determining EphA1 as the research object, by analyzing research articles on EphA1 in the PubMed system in recent 10 years, we found that EphA1 was closely connected with the occurrence and development of tumors and further determined the references according to the influencing factors for review and analysis. RESULTS: EphA1 has been identified as a cancer protein in various tumors, such as hepatocellular carcinoma, nasopharyngeal carcinoma, ovarian cancer, gastric cancer, colorectal cancer, clear cell renal cell carcinoma, esophageal squamous cell carcinoma, breast cancer, prostate cancer and uveal melanoma. EphA1 is abnormally expressed in these tumor cells, which mainly plays a role in cancer progression, tumor angiogenesis, intestinal environmental stability, the lymph node system, nervous system diseases and gynecological diseases. In a narrow sense, EphA1 is especially effective in breast cancer in terms of gynecological diseases. However, the specific mechanism of EphA1 leading to the change of cancer cells in some tumors is not clear, which needs further research and exploration. CONCLUSION: RTK EphA1 can be used as a biomarker for tumor diagnosis (especially a prognostic marker), an indispensable therapeutic target for new anti-tumor therapies, and a novel anti-tumor drug.
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Neoplasias de la Mama , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Receptor EphA2 , Embarazo , Masculino , Humanos , Femenino , Receptor EphA1/genética , Receptor EphA1/análisis , Receptor EphA1/metabolismo , Efrina-A1/metabolismo , Ligandos , Placenta/química , Placenta/metabolismo , Efrinas/genética , Efrinas/análisis , Efrinas/metabolismo , Receptores de la Familia Eph/genética , Receptores de la Familia Eph/metabolismo , Biomarcadores , Receptor EphA2/metabolismoRESUMEN
The eye lens is a transparent, ellipsoid organ in the anterior chamber of the eye that is required for fine focusing of light onto the retina to transmit a clear image. Cataracts, defined as any opacity in the lens, remains the leading cause of blindness in the world. Recent studies in humans and mice indicate that Eph-ephrin bidirectional signaling is important for maintaining lens transparency. Specifically, mutations and polymorphisms in the EphA2 receptor and the ephrin-A5 ligand have been linked to congenital and age-related cataracts. It is unclear what other variants of Ephs and ephrins are expressed in the lens or whether there is preferential expression in epithelial vs. fiber cells. We performed a detailed analysis of Eph receptor and ephrin ligand mRNA transcripts in whole mouse lenses, epithelial cell fractions, and fiber cell fractions using a new RNA isolation method. We compared control samples with EphA2 knockout (KO) and ephrin-A5 KO samples. Our results revealed the presence of transcripts for 12 out of 14 Eph receptors and 8 out of 8 ephrin ligands in various fractions of lens cells. Using specific primer sets, RT-PCR, and sequencing, we verified the variant of each gene that is expressed, and we found two epithelial-cell-specific genes. Surprisingly, we also identified one Eph receptor variant that is expressed in KO lens fibers but is absent from control lens fibers. We also identified one low expression ephrin variant that is only expressed in ephrin-A5 control samples. These results indicate that the lens expresses almost all Ephs and ephrins, and there may be many receptor-ligand pairs that play a role in lens homeostasis.
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Catarata , Cristalino , Receptor EphA2 , Humanos , Ratones , Animales , Efrinas/genética , Efrinas/metabolismo , Receptor EphA1/metabolismo , Efrina-A5/genética , Efrina-A5/metabolismo , Ligandos , Receptor EphA2/genética , Receptor EphA2/metabolismo , Cristalino/metabolismo , Receptores de la Familia Eph/genética , Receptores de la Familia Eph/metabolismo , Catarata/genética , ARN Mensajero/metabolismoRESUMEN
Port-wine stains (PWSs) are congenital vascular malformations that involve the skin and mucosa. To date, the mechanisms underlying the pathogenesis and progression of PWSs are yet to be clearly elucidated. The potential reasons for dilated vessels are as follows: (1) somatic GNAQ (R183Q) mutations that form enlarged capillary malformation-like vessels through angiopoietin-2, (2) decreased perivascular nerve elements, (3) the coexistence of Eph receptor B1 and ephrin B2, and (4) the deficiency of αSMA expression in pericytes. In addition, ERK, c-JNK, P70S6K, AKT, PI3K, and PKC are assumed to be involved in PWS development. Although pulsed-dye laser (PDL) remains the gold standard for treating PWSs, the recurrence rate is high. Topical drugs, including imiquimod, axitinib, and rapamycin, combined with PDL treatments, are expected to alter the recurrence rate and reduce the number of PDL sessions for PWSs. For the deep vascular plexus, photosensitizers or photothermal transduction agents encapsulated by nanocarriers conjugated to surface markers (CD133/CD166/VEGFR-2) possess a promising therapeutic potential in photodynamic therapy or photothermal therapy for PWSs. The pathogenesis, progression, and treatment of PWSs should be extensively investigated.
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Mancha Vino de Oporto , Humanos , Mancha Vino de Oporto/genética , Mancha Vino de Oporto/terapia , Proteínas Quinasas S6 Ribosómicas 70-kDa , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Angiopoyetina 2 , Imiquimod , Fármacos Fotosensibilizantes/uso terapéutico , Efrina-B2 , Axitinib , Proteínas Proto-Oncogénicas c-akt , Receptor EphA1 , Sirolimus/uso terapéutico , Fosfatidilinositol 3-Quinasas , Resultado del TratamientoRESUMEN
While the typical role of receptor tyrosine kinases is to receive and transmit signals at the cell surface, in some cellular contexts (particularly transformed cells) they may also act as nuclear proteins. Aberrant nuclear localization of receptor tyrosine kinases associated with transformation often enhances the transformed phenotype (i.e. nuclear ErbBs promote tumor progression in breast cancer). Rhabdomyosarcoma (RMS), the most common soft tissue tumor in children, develops to resemble immature skeletal muscle and has been proposed to derive from muscle stem/progenitor cells (satellite cells). It is an aggressive cancer with a 5-year survival rate of 33% if it has metastasized. Eph receptor tyrosine kinases have been implicated in the development and progression of many other tumor types, but there are only two published studies of Ephs localizing to the nucleus of any cell type and to date no nuclear RTKs have been identified in RMS. In a screen for protein expression of Ephs in canine RMS primary tumors as well as mouse and human RMS cell lines, we noted strong expression of EphA1 in the nucleus of interphase cells in tumors from all three species. This localization pattern changes in dividing cells, with EphA1 localizing to the nucleus or the cytoplasm depending on the phase of the cell cycle. These data represent the first case of a nuclear RTK in RMS, and the first time that EphA1 has been detected in the nucleus of any cell type.
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Receptor EphA1 , Rabdomiosarcoma , Animales , Niño , Perros , Humanos , Ratones , Músculo Esquelético , Proteínas Nucleares , Receptor EphA1/genética , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , TirosinaRESUMEN
The receptor tyrosine kinase EPHB2 (EPH receptor B2) is highly expressed in many human cancer types, especially in gastrointestinal cancers, such as colorectal cancer. Several coding mutations of the EPHB2 gene have been identified in many cancer types, suggesting that EPHB2 plays a critical role in carcinogenesis. However, the exact functional mechanism of EPHB2 in carcinogenesis remains unknown. In this study, we find that EPHB2 is required for TNF-induced signaling activation and proinflammatory cytokine production in colorectal epithelial cells. Mechanistically, after TNF stimulation, EPHB2 is ubiquitinated by its E3 ligase RNF186. Then, ubiquitinated EPHB2 recruits and further phosphorylates TAB2 at nine tyrosine sites, which is a critical step for the binding between TAB2 and TAK1. Due to defects in TNF signaling in RNF186-knockout colorectal epithelial cells, the phenotype of colitis-propelled colorectal cancer model in RNF186-knockout mice is significantly reduced compared with that in wild-type control mice. Moreover, we find that a genetic mutation in EPHB2 identified in a family with colorectal cancer is a gain-of-function mutation that promoted TNF signaling activation compared with wild-type EPHB2. We provide evidence that the EPHB2-RNF186-TAB2-TAK1 signaling cascade plays an essential role in TNF-mediated signal transduction in colorectal epithelial cells and the carcinogenesis of colorectal cancer, which may provide potential targets for the treatment of colorectal cancer.
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Neoplasias Colorrectales , Receptor EphA1 , Animales , Humanos , Ratones , Carcinogénesis , Neoplasias Colorrectales/genética , Citocinas , Células Epiteliales/metabolismo , Receptor EphA1/metabolismo , Transducción de Señal , Tirosina , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Receptor EphB2Asunto(s)
Enfermedades Desmielinizantes , Receptor EphA1 , Axones , Depresión , Humanos , Receptor EphA4RESUMEN
OBJECTIVE: This study intends to conquer the mystery of microRNA-16-5p/erythropoietin-producing hepatocellular A1/nuclear factor-κB signaling (miR-16-5p/EPHA1/NF-κB signaling) in breast cancer. METHODS: Expression of miR-16-5p, EPHA1 and NF-κB signaling-related proteins were detected. Gene overexpression or silencing was used to examine the biological roles of bone marrow mesenchymal stem cells (BMSCs)-derived exo-miR-16-5p in breast cancer. The effect of exo-miR-16-5p on tumorigenesis of breast cancer was confirmed by the xenograft nude mouse model. RESULTS: Low miR-16-5p and high EPHA1 expression were examined in breast cancer. BMSCs-derived exosomes, up-regulated miR-16-5p or down-regulated EPHA1 restrained epithelial-mesenchymal transition (EMT) of breast cancer cells and tumor growth in nude mice. Down-regulated miR-16-5p or up-regulated EPHA1 activated NF-κB signaling. Knockdown of EPHA1 or inhibition of NF-κB signaling reversed the effects of down-regulated miR-16-5p on breast cancer cells. CONCLUSION: BMSCs-derived exosomal miR-16-5p hinders breast cancer cells progression via EPHA1/NF-κB signaling axis.
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Células Madre Mesenquimatosas , MicroARNs , Neoplasias , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal , Células Madre Mesenquimatosas/metabolismo , Ratones Desnudos , MicroARNs/genética , MicroARNs/metabolismo , Neoplasias/metabolismo , FN-kappa B/metabolismo , Receptor EphA1/metabolismoRESUMEN
ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior. Specific depletion of Ash1l in forebrain induces similar ASD-associated behavioral defects. While the learning ability remains intact, the discrimination ability of Ash1l mutant mice is reduced. Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period. Dysregulation of synaptic genes is detected in Ash1l mutant brain. Specifically, Eph receptor A7 is downregulated in Ash1l+/- mice through accumulating EZH2-mediated H3K27me3 in its gene body. Importantly, increasing activation of EphA7 in Ash1l+/- mice by supplying its ligand, ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits. Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for ASD, resulting from synapse pruning deficits.
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Trastorno del Espectro Autista , Trastorno Autístico , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/metabolismo , Trastorno Autístico/genética , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Haploinsuficiencia , N-Metiltransferasa de Histona-Lisina/genética , Ratones , Ratones Noqueados , Fenotipo , Receptor EphA1RESUMEN
MicroRNAs (miRNAs) have critical roles in colorectal cancer (CRC) tumorigenesis and development. It has been reported that Eph receptor A7 (EphA7) was a potential target of miR-944 which is transcriptionally activated in cancer. The aim of this study was to explore the expression profile of miR-944 and its target gene EPHA7 in the serum of Egyptian CRC patients. 150 CRC patients, 50 adenomatous polyps (AP) patients, and 100 healthy controls were included. Serum miR-944 was downregulated (0.304 ± 0.0512) while serum EPHA7 was upregulated (3.163 ± 0.610) in CRC and AP patients versus controls and discriminated aganst these groups by Receiver operating characteristic curve (ROC) analysis. miR-944 presented the highest diagnostic accuracy for CRC patients from control (AUC = 0.90). Moreover obvious prognostic power in distinguishing AP from CRC (AUC = 0.87). In conclusion, miR-944 and EPHA7 are potential genetic markers of CRC predisposition and novel potential non-invasive diagnostic biomarkers for CRC.
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MicroARN Circulante , Neoplasias Colorrectales , MicroARNs , Biomarcadores de Tumor/genética , MicroARN Circulante/genética , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica , Marcadores Genéticos , Humanos , MicroARNs/genética , Receptor EphA1/genética , Receptor EphA7RESUMEN
BACKGROUND: No biomarkers have been identified that can classify subtypes of hand eczema (HE). Although skin biopsies represent the gold standard for investigations of the skin, the invasive technique is not favorable when investigating skin from sensitive areas. Recent advances in the use of skin-tape strips for molecular investigations enable noninvasive investigations of HE. OBJECTIVE: By using whole transcriptome sequencing (WTS), the molecular profile of HE according to different localizations on the hands, etiologies, and clinical/morphological subtypes was investigated. METHODS: Thirty adult, Danish HE patients, 12 with and 18 without concurrent atopic dermatitis (AD), as well as 16 controls were included. Tape strip samples were collected from lesional, nonlesional, and healthy skin. Total RNA was extracted and WTS was performed. RESULTS: The largest molecular difference of HE patients with and without AD was found in nonlesional skin areas and included a downregulation of CXCL8 for HE patients without AD. Differences between allergic and irritant contact dermatitis included epidermal biomarkers such as EPHA1. CONCLUSION: Skin tape strip samples could be used to assess the gene expression profile of HE on different localizations of the hands. The skin tape strip method identified new molecular markers that showed promising result for the identification of HE subtypes.
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Dermatosis de la Mano/diagnóstico , Dermatosis de la Mano/genética , Manejo de Especímenes/métodos , Cinta Quirúrgica , Transcriptoma , Adulto , Anciano , Biomarcadores/metabolismo , Dermatitis Alérgica por Contacto/diagnóstico , Dermatitis Alérgica por Contacto/genética , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/genética , Dermatitis Irritante/diagnóstico , Dermatitis Irritante/genética , Diagnóstico Diferencial , Regulación hacia Abajo , Femenino , Dermatosis de la Mano/inmunología , Humanos , Interleucina-8/metabolismo , Masculino , Persona de Mediana Edad , Receptor EphA1/metabolismo , Piel/inmunología , Piel/metabolismo , Secuenciación del ExomaRESUMEN
Autonomous heavy-chain variable (VH) domains are the smallest functional antibody fragments, and they possess unique features, including small size and convex paratopes, which provide enhanced targeting of concave epitopes that are difficult to access with larger conventional antibodies. However, human VH domains have evolved to fold and function with a light chain partner, and alone, they typically suffer from low stability and high aggregation propensity. Development of autonomous human VH domains, in which aggregation propensity is reduced without compromising antigen recognition, has proven challenging. Here, we used an autonomous human VH domain as a scaffold to construct phage-displayed synthetic libraries in which aspartate was systematically incorporated at different paratope positions. In selections, the library yielded many anti-EphA1 receptor VH domains, which were characterized in detail. Structural analyses of a parental anti-EphA1 VH domain and an improved variant provided insights into the effects of aspartate and other substitutions on preventing aggregation while retaining function. Our naïve libraries and in vitro selection procedures offer a systematic approach to generating highly functional autonomous human VH domains that resist aggregation and could be used for basic research and biomedical applications.