RESUMEN
Tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) type IIb are the predominant causes of drug-refractory epilepsy in children. Dysmorphic neurons (DNs), giant cells (GCs), and balloon cells (BCs) are the most typical pathogenic profiles in cortical lesions of TSC and FCD IIb patients. However, mechanisms underlying the pathological processes of TSC and FCD IIb remain obscure. The Plexin-B2-Sema4C signalling pathway plays critical roles in neuronal morphogenesis and corticogenesis during the development of the central nervous system. However, the role of the Plexin-B2 system in the pathogenic process of TSC and FCD IIb has not been identified. In the present study, we investigated the expression and cell distribution characteristics of Plexin-B2 and Sema4C in TSC and FCD IIb lesions with molecular technologies. Our results showed that the mRNA and protein levels of Plexin-B2 expression were significantly increased both in TSC and FCD IIb lesions versus that in the control cortex. Notably, Plexin-B2 was also predominantly observed in GCs in TSC epileptic lesions and BCs in FCD IIb lesions. In contrast, the expression of Sema4C, the ligand of Plexin-B2, was significantly decreased in DNs, GCs, and BCs in TSC and FCD IIb epileptic lesions. Additionally, Plexin-B2 and Sema4C were expressed in astrocytes and microglia cells in TSC and FCD IIb lesions. Furthermore, the expression of Plexin-B2 was positively correlated with seizure frequency in TSC and FCD IIb patients. In conclusion, our results showed the Plexin-B2-Sema4C system was abnormally expressed in cortical lesions of TSC and FCD IIb patients, signifying that the Plexin-B2-Sema4C system may play a role in the pathogenic development of TSC and FCD IIb.
Asunto(s)
Displasia Cortical Focal , Malformaciones del Desarrollo Cortical de Grupo I , Proteínas del Tejido Nervioso , Semaforinas , Esclerosis Tuberosa , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Epilepsia Refractaria/metabolismo , Epilepsia Refractaria/patología , Epilepsia , Displasia Cortical Focal/metabolismo , Displasia Cortical Focal/patología , Células Gigantes/metabolismo , Células Gigantes/patología , Malformaciones del Desarrollo Cortical de Grupo I/metabolismo , Malformaciones del Desarrollo Cortical de Grupo I/patología , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/biosíntesis , Neuronas/metabolismo , Neuronas/patología , Semaforinas/metabolismo , Semaforinas/genética , Semaforinas/biosíntesis , Esclerosis Tuberosa/metabolismo , Esclerosis Tuberosa/patologíaRESUMEN
Semaphorin 4D (Sema4D) is highly expressed in a variety of tumors and is associated with high invasion, poor prognosis and poor therapeutic response. However, the expression and role of Sema4D in leukemia remains unclear. The present study investigated the expression of Sema4D in pediatric leukemia and its effects in leukemia cells. The results demonstrated that Sema4D protein was highly expressed in peripheral blood mononuclear cells of patients with pediatric leukemia, and high levels of soluble Sema4D were also observed in the plasma of these patients. Sema4D knockdown induced cell cycle arrest in G0/G1 phase, inhibited proliferation and promoted apoptosis in BALL1 cells, while Sema4D overexpression exhibited the opposite effect. In Jurkat cells, Sema4D knockdown inhibited proliferation and promoted apoptosis, while Sema4D overexpression decreased the abundance of the cells in the G0/G1 phase of the cell cycle and promoted proliferation. Sema4D overexpression also increased the migratory capacity of Jurkat cells and the invasive capacity of BALL1 cells. The phosphorylation level of PI3K was decreased in both Sema4D knockeddown Jurkat and BALL1 cells, and the phosphorylation level of ERK was decreased in Sema4D knockeddown BALL1 cells. The phosphorylation levels of PI3K, ERK and AKT were elevated in patients with pediatric leukemia, and were correlated to the increased Sema4D expression. Sema4D overexpression was associated with a shorter overall survival in patients with acute myeloid leukemia. Overall, the results of the present study indicated that Sema4D serves an important role in leukemia development by activating PI3K/AKT and ERK signaling, and it may be used as a potential target for the diagnosis and treatment of leukemia.
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Antígenos CD/sangre , Leucemia Mieloide Aguda/metabolismo , Sistema de Señalización de MAP Quinasas , Fosfatidilinositol 3-Quinasas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Semaforinas/sangre , Adolescente , Antígenos CD/biosíntesis , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Línea Celular Tumoral , Proliferación Celular/fisiología , Niño , Preescolar , Femenino , Humanos , Lactante , Células Jurkat , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/patología , Leucocitos Mononucleares/metabolismo , Masculino , Fosforilación , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Semaforinas/biosíntesisRESUMEN
OBJECTIVE: In this study, we explored the effect of semaphorin5A (SEMA5A) on RA pathogenesis and its specific TSP1 domain on pannus formation. METHODS: The expression of SEMA5A was detected in the synovium, the fibroblast-like synoviocytes (FLSs) and the SF of RA patients and healthy controls (HCs) by real-time quantitative PCR (q-PCR), immunohistochemistry staining, western blot and ELISA. SEMA5A-mAb intervention was performed to appraise the severity of joints in the CIA model. Transcriptome sequencing and bioinformatics analysis in SEMA5A-transfected FLSs from HCs were performed to screen differentially expressed genes after SEMA5A overexpression. An MTT assay in RA-FLSs, a chicken embryo allantoic membrane experiment and a tube formation experiment were used to clarify the influence of SEMA5A on cell proliferation and angiogenesis. Furthermore, a rescue experiment verified the function of the TSP1 domain of SEMA5A in the progress of RA with Sema5a-/- CIA mice. RESULTS: The expression of SEMA5A increased in RA compared with that in HCs. Simultaneously, SEMA5A-mAbs significantly attenuated joint injury and the inflammatory response in CIA models. In addition, transcriptome sequencing and angiogenesis-related experiments verified the ability of SEMA5A to promote FLS proliferation and angiogenesis. Moreover, TSP1 was proved to be an essential domain in SEMA5A-induced angiogenesis in vitro. Additionally, rescue of TSP1-deleted SEMA5A failed to reduce the severity of arthritis in a CIA model constructed with Sema5a -/- mice. CONCLUSION: In summary, upregulation of SEMA5A was first confirmed in pathological lesions of RA patients. Furthermore, treatment with SEMA5A-mAbs attenuated the progress of RA in the CIA model. Moreover, TSP1 was indicated as the key domain of SEMA5A in the promotion of pannus formation in RA.
Asunto(s)
Artritis Experimental/genética , Artritis Reumatoide/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Regulación de la Expresión Génica , ARN/genética , Semaforinas/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/biosíntesis , Western Blotting , Movimiento Celular , Proliferación Celular , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Estudios de Seguimiento , Secuencias Hélice-Asa-Hélice , Humanos , Masculino , Ratones , Ratones Endogámicos DBA , Persona de Mediana Edad , Estudios Retrospectivos , Semaforinas/biosíntesis , Sinoviocitos/metabolismo , Sinoviocitos/patología , Trombospondina 1RESUMEN
Overexpression of semaphorin 4D (SEMA4D), an immune semaphorin, is found in various human malignancies, including colorectal cancer (CRC). In this study, we explored the relationship between silencing SEMA4D expression and 5-fluorouracil (5-FU) response in the colorectal cancer cell line. SW48 cells were transfected with a short interfering RNA (siRNA) in order to silence SEMA4D gene expression and then exposed to 5-FU for 48 h. The down-regulation of SEMA4D expression was confirmed by qRT-PCR and the particular concentration of 5-FU was acquired using MTT assay. Flow cytometry and western blot were used to evaluate apoptosis rate and pro- and anti-apoptotic expression levels of proteins involved in apoptosis including Bax, Bcl-2, P53, and caspase-3. Other oncogenic activities including epithelial-mesenchymal transition (EMT) process, cancer stem cell (CSC) markers, and ß-catenin pathway were investigated using qRT-PCR, and western blot. The proliferation was analyzed via colony formation test and cell invasion was assessed by transwell assay. Our data demonstrate that SEMA4D silencing results in strikingly elevated apoptosis in response to 5-FU treatment and leads to down-regulation of Bcl-2 and overexpression of Bax, P53, and caspase-3 in protein levels. Furthermore, the mRNA and protein expression levels of ß-catenin, as well as transcript expressions of CSCs and EMT markers, were remarkably diminished. However, mRNA expression of E-cadherin as an epithelial marker was significantly increased in 5-FU treatment combined with siRNA SEMA4D. This study implicates that the silencing of SEMA4D by siRNA promotes the chemosensitivity of SW48 cells to 5-FU and it may be a potential therapeutic agent for colon cancer therapy.
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Antígenos CD/biosíntesis , Apoptosis/efectos de los fármacos , Neoplasias Colorrectales/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Fluorouracilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Proteínas de Neoplasias/biosíntesis , Semaforinas/biosíntesis , Antígenos CD/genética , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Humanos , Proteínas de Neoplasias/genética , Semaforinas/genéticaRESUMEN
Axon regeneration is limited in the central nervous system, which hinders the reconstruction of functional circuits following spinal cord injury (SCI). Although various extrinsic molecules to repel axons following SCI have been identified, the role of semaphorins, a major class of axon guidance molecules, has not been thoroughly explored. Here we show that expression of semaphorins, including Sema5a and Sema6d, is elevated after SCI, and genetic deletion of either molecule or their receptors (neuropilin1 and plexinA1, respectively) suppresses axon retraction or dieback in injured corticospinal neurons. We further show that Olig2+ cells are essential for SCI-induced semaphorin expression, and that Olig2 binds to putative enhancer regions of the semaphorin genes. Finally, conditional deletion of Olig2 in the spinal cord reduces the expression of semaphorins, alleviating the axon retraction. These results demonstrate that semaphorins function as axon repellents following SCI, and reveal a novel transcriptional mechanism for controlling semaphorin levels around injured neurons to create zones hostile to axon regrowth.
Asunto(s)
Regulación de la Expresión Génica/fisiología , Regeneración Nerviosa/fisiología , Factor de Transcripción 2 de los Oligodendrocitos/metabolismo , Semaforinas/biosíntesis , Traumatismos de la Médula Espinal/metabolismo , Animales , Axones/patología , Ratones , Ratones Endogámicos C57BL , Tractos Piramidales/lesiones , Tractos Piramidales/metabolismo , Traumatismos de la Médula Espinal/patologíaRESUMEN
BACKGROUND: The aim of this study was to detect the expression of long noncoding RNA small nucleolar RNA host gene 18 (SNHG18) andsemaphorin 5A (SEMA5A) genes in multiple myeloma (MM) patients and to explore the correlation of the expression of these genes with the clinical characteristics and prognosis of MM patients. METHODS: Forty-seven newly diagnosed MM, 18 complete remission MM, 13 refractory/relapse MM, and 22 iron deficiency anemia (serving as control) samples were extracted at the Department of Hematology, Second Aï¬liated Hospital of Xian Jiaotong University between January 2015 and December 2016. The clinical features of the MM patients are summarized. Real-time quantitative PCR was performed to analyze the relative expression levels of the SNHG18 and SEMA5Agenes. The clinical characteristics and overall survival (OS) of the MM patients were statistically analyzed while measuring different levels of SNHG18 and SEMA5Agene expression. At the same time, the correlation between the expression of SNHG18 and SEMA5A was also analyzed. RESULTS: The analysis confirmed that SNHG18 and its possible target gene SEMA5A were both highly expressed in newly diagnosed MM patients. After analyzing the clinical signiï¬cance of SNHG18 and SEMA5A in MM patients, we found that the expression of SNHG18 and SEMA5A was related to the Durie-Salmon (DS), International Staging System (ISS), and Revised International Staging System (R-ISS) classification systems, and the Mayo Clinic Risk Stratification for Multiple Myeloma (mSMART; p < 0.05). Moreover, we observed a significant difference in OS between the SNHG18/SEMA5A high expression group and the low expression group. We found a positive correlation between SNHG18 and SEMA5A expression (r = 0.709, p < 0.01). Surprisingly, the expected median OS times of both the SNHG18 and SEMA5Ahigh expression groups were significantly decreased, which was in contrast to those of both the SNHG18 and SEMA5Alow expression groups and the single-gene high expression group (p < 0.05). CONCLUSION: High expression of both SNHG18 and SEMA5A is associated with poor prognosis in patients with MM.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Mieloma Múltiple/sangre , Proteínas de Neoplasias/sangre , ARN Largo no Codificante/sangre , ARN Neoplásico/sangre , Semaforinas/sangre , Adulto , Anciano , Anemia Ferropénica/sangre , Anemia Ferropénica/genética , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mieloma Múltiple/genética , Mieloma Múltiple/mortalidad , Mieloma Múltiple/patología , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/genética , Estadificación de Neoplasias , Pronóstico , ARN Largo no Codificante/biosíntesis , ARN Largo no Codificante/genética , ARN Neoplásico/biosíntesis , ARN Neoplásico/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Recurrencia , Inducción de Remisión , Semaforinas/biosíntesis , Semaforinas/genéticaRESUMEN
Guidance cues act during development to guide growth cones to their proper targets in both the central and peripheral nervous systems. Experiments in many species indicate that guidance molecules also play important roles after development, though less is understood about their functions in the adult. The Semaphorin family of guidance cues, signaling through Plexin receptors, influences the development of both axons and dendrites in invertebrates. Semaphorin functions have been extensively explored in Drosophila melanogaster and some other Dipteran species, but little is known about their function in hemimetabolous insects. Here, we characterize sema1a and plexA in the cricket Gryllus bimaculatus. In fact, we found two distinct predicted Sema1a proteins in this species, Sema1a.1 and Sema1a.2, which shared only 48% identity at the amino acid level. We include a phylogenetic analysis that predicted that many other insect species, both holometabolous and hemimetabolous, express two Sema1a proteins as well. Finally, we used in situ hybridization to show that sema1a.1 and sema1a.2 expression patterns were spatially distinct in the embryo, and both roughly overlap with plexA. All three transcripts were also expressed in the adult brain, mainly in the mushroom bodies, though sema1a.2 was expressed most robustly. sema1a.2 was also expressed strongly in the adult thoracic ganglia while sema1a.1 was only weakly expressed and plexA was undetectable.
Asunto(s)
Proteínas de Drosophila/biosíntesis , Proteínas de Drosophila/genética , Gryllidae/crecimiento & desarrollo , Gryllidae/genética , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/genética , Semaforinas/biosíntesis , Semaforinas/genética , Factores de Edad , Secuencia de Aminoácidos , Animales , Regulación del Desarrollo de la Expresión Génica , Gryllidae/metabolismo , FilogeniaRESUMEN
Cell migration is a fundamental feature of cancer recurrence. Since recurrence is correlated with high mortality in lung cancer, it follows that reducing cell migration would decrease recurrence and increase survival rates. Semaphorin-6A (SEMA6A), a protein initially known as a regulator of axonal guidance, is down-regulated in lung cancer tissue, and low levels of SEMA6A are associated with cancer recurrence. Thus, we hypothesized that SEMA6A could suppress cancer cell migration. In this study, we found that the migration capability of H1299 lung cancer cells decreased with SEMA6A overexpression, while it increased with SEMA6A silencing. Moreover, silencing of the cellular homeostasis protein Heme-oxygenase-1 (HMOX1) and/or the transcription factor Nuclear Factor, Erythroid-2-Like-2 (NRF2) reversed the migration-suppressing effect of SEMA6A and the SEMA6A-driven alterations in expression of urokinase insulin-like-growth-factor-binding-protein-3, Matrix metalloproteinase (MMP)-1, and MMP9, the downstream effectors of HMOX1. Taken together, these results demonstrate that SEMA6A is a potential suppressor of cancer migration that functions through the NRF2/HMOX1 axis. Our results explain why low SEMA6A is linked to high recurrence in the clinical setting and suggest that SEMA6A could be useful as a biomarker or target in lung cancer therapy.
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Hemo-Oxigenasa 1/metabolismo , Neoplasias Pulmonares/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Semaforinas/metabolismo , Línea Celular Tumoral , Movimiento Celular/fisiología , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Semaforinas/biosíntesis , Semaforinas/genética , Transducción de SeñalRESUMEN
Semaphorins are a large family of evolutionarily conserved morphogenetic molecules that are associated with repelling axonal guidance. Intriguingly, recent researches indicate that semaphorins are involved in cancer progression. Semaphorin 4C (SEMA4C) has long been considered a neuronal migration gene, but we detected that it is also highly expressed in many malignant human cancers. During an investigation of subcutaneous tumor models, we found that SEMA4C expression promoted tumor growth and progression. We discovered that SEMA4C was involved in maintaining tumor cell self-renewal, likely by regulating the p53 pathway. Inhibiting the expression of endogenous SEMA4C in tumor cells impaired growth and induced senescence and cell-cycle arrest in the G2-phase. In addition, we found that SEMA4C induced the production of angiogenin and colony-stimulating factor-1 (CSF-1) in tumor cells by activating the NF-κB pathway in a plexinB2-dependent manner. In conclusion, SEMA4C expression in breast cancer cells promotes cancer cell proliferation, macrophage recruitment, and angiogenesis. Thus, inhibition of SEMA4C activity may be a novel therapeutic strategy for human breast cancer. IMPLICATIONS: In breast cancer, therapeutic targeting of the SEMA4C pathway may prevent tumor growth, angiogenesis, metastasis, and progression.
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Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Semaforinas/metabolismo , Células A549 , Adenofibroma/irrigación sanguínea , Adenofibroma/genética , Adenofibroma/metabolismo , Adenofibroma/patología , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Células HT29 , Células HeLa , Xenoinjertos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Proteínas del Tejido Nervioso/metabolismo , Semaforinas/biosíntesis , Semaforinas/genética , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is one of the most lethal cancers mainly due to the high rate of metastasis. Here, we find that the expression level of CD100 in HNSCC is positively correlated with the T category, pathological grade and lymph node metastasis of the tumor. The level of soluble CD100 (sCD100) is highly increased in serum of HNSCC patients, and sCD100 markedly induces the epithelial-mesenchymal transition (EMT) of HNSCC through its receptor, Plexin-B1 (PlxnB1), and promotes the metastasis in a xenograft mouse model. Furthermore, sCD100 promotes the stabilization of Snail through the regulation of the Vav1-Rac1/RhoA-p21-activated kinase pathway for the induction of EMT. Anti-CD100 antibody abolishes the CD100-induced EMT and prevents the metastasis of HNSCC, and anti-CD100 antibody also increases the drug sensitivity of HNSCC. Taken together, our study shows for the first time that CD100 induces the EMT of HNSCC and promotes the metastasis, and CD100 would be a candidate as a novel prognostic biomarker and a potential therapeutic target for HNSCC.
Asunto(s)
Antígenos CD/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Proteínas del Tejido Nervioso/metabolismo , Receptores de Superficie Celular/metabolismo , Semaforinas/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Animales , Antígenos CD/biosíntesis , Antígenos CD/sangre , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Transición Epitelial-Mesenquimal , Femenino , Neoplasias de Cabeza y Cuello/sangre , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Metástasis de la Neoplasia , Estadificación de Neoplasias , Proteínas del Tejido Nervioso/biosíntesis , Receptores de Superficie Celular/biosíntesis , Semaforinas/biosíntesis , Semaforinas/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/sangreRESUMEN
Frequent deletions of tumor-suppressor genes at chromosome 3p21.3 have been detected in esophageal squamous cell carcinoma (ESCC). As a candidate tumor suppressor gene, semaphorin 3B (SEMA3B) is located at 3p21.3 and is frequently inactivated in several tumors. However, the role and inactivation mechanisms of SEMA3B and its antisense long non-coding RNA (lncRNA) SEMA3B-AS1 in the carcinogenesis of ESCC have not been fully elucidated. The present study was conducted to investigate the role, epigenetic inactivation mechanisms, and prognostic value of SEMA3B and SEMA3B-AS1 in ESCC tumorigenesis and prognosis. Frequent downregulation of SEMA3B and SEMA3B-AS1 was detected in esophageal cancer cells and ESCC tissues, and the expression level of SEMA3B and SEMA3B-AS1 in ESCC tissues was correlated with TNM stage and lymph node metastasis. SEMA3B and SEMA3B-AS1 shared the same CpG island in the promoter region and the expression of both genes might be regulated by the promoter methylation status. Furthermore, transcription factor Sp1 activated SEMA3B or SEMA3B-AS1 transcription and the promoter hypermethylation of SEMA3B and SEMA3B-AS1 influenced Sp1 binding ability. Moreover, over-expression of SEMA3B and SEMA3B-AS1 suppressed the viability and invasion of esophageal cancer cells in vitro. SEMA3B-AS1 influenced the protein expression of SEMA3B. SEMA3B or SEMA3B-AS1 expression and promoter methylation status were correlated with ESCC patients' survival. Thus, these findings suggest that SEMA3B and SEMA3B-AS1 may act as tumor suppressors and may serve as potential targets for antitumor therapy.
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Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Glicoproteínas de Membrana/genética , ARN Largo no Codificante/genética , Semaforinas/genética , Adulto , Anciano , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Proliferación Celular/genética , Transformación Celular Neoplásica/genética , Metilación de ADN/genética , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Genes Supresores de Tumor , Humanos , Masculino , Glicoproteínas de Membrana/biosíntesis , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas/genética , Semaforinas/biosíntesisRESUMEN
INTRODUCTION: SEMA4D and its high affinity receptor Plexin-B1 showed a promising prognosis prediction for carcinoma patients in recent studies, we performed a meta-analysis to evaluate the prognostic role of them in various malignancies. METHODS: A systematic literature search was performed in PubMed, Embase, Web of Science, and CNKI from inception till July 2017. Eligible studies were identified by different reviewers. Hazard ratios (HRs)/related ratios (RRs) and their corresponding 95% confidence intervals (CIs) were extracted to investigate the relevance between malignancies prognosis and SEMA4D/Plexin-B1. RESULTS: Around 2638 patients from 14 studies were included in this meta-analysis. High expression of SEMA4D was significantly associated with overall survival (OS) and disease-free survival/progression-free survival/recurrence-free survival (DFS/PFS/RFS) in tumors (respectively, HRosâ=â2.05, 95%CI: 1.68-2.50, Pâ<â.001; HRdfs/pfs/rfsâ=â1.59, 95%CIâ=â1.27-1.98, Pâ<â.001). However, the relationship between SEMA4D expression and prognosis of breast cancer patients was failed to find (HRâ=â0.76, 95%CIâ=â0.32-1.82, Pâ=â.539). Plexin-B1 level showed a significant positive correlation both with OS and DFS of Caucasian breast cancer patients (respectively, HRosâ=â0.56, 95%CI: 0.39-0.79, Pâ=â.001; HRdfsâ=â0.68, 95%CIâ=â0.51-0.90, Pâ=â.008) CONCLUSIONS:: SEMA4D could be a prospective biomarker for prognostic prediction of various malignancies except breast cancer. For Caucasian breast cancer patients, SEMA4D's high affinity receptor Plexin-B1 showed a significant positive correlation with survival.
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Antígenos CD/biosíntesis , Neoplasias/genética , Neoplasias/mortalidad , Proteínas del Tejido Nervioso/biosíntesis , Receptores de Superficie Celular/biosíntesis , Semaforinas/biosíntesis , Biomarcadores de Tumor , Neoplasias de la Mama/genética , Supervivencia sin Enfermedad , Humanos , Pronóstico , Modelos de Riesgos Proporcionales , Estudios ProspectivosRESUMEN
Class III Semaphorin (Sema) secreted ligands are known to repel neurites expressing Neuropilin (Nrp) and/or Plexin (Plxn) receptors. There is, however, a growing body of literature supporting that Sema signaling also has alternative roles in development such as synaptogenesis, boundary formation, and vasculogenesis. To evaluate these options during inner ear development, we used in situ hybridization or immunohistochemistry to map the expression of Sema3D, Sema3F, Nrp1, Nrp2, and PlxnA1 in the chicken (Gallus gallus) inner ear from embryonic day (E)5-E10. The resulting expression patterns in either the otic epithelium or its surrounding mesenchyme suggest that Sema signaling could be involved in each of the varied functions reported for other tissues. Sema3D expression flanking the sensory tissue in vestibular organs suggests that it may repel Nrp2- and PlxnA1-expressing neurites of the vestibular ganglion away from nonsensory epithelia, thus channeling them into the sensory domains at E5-E8. Expression of Sema signaling genes in the sensory hair cells of both the auditory and vestibular organs on E8-E10 may implicate Sema signaling in synaptogenesis. In the nonsensory regions of the cochlea, Sema3D in the future tegmentum vasculosum opposes Nrp1 and PlxnA1 in the future cuboidal cells; the abutment of ligand and receptors in adjacent domains may enforce or maintain the boundary between them. In the mesenchyme, Nrp1 colocalized with capillary-rich tissue. Sema3D immediately flanks this Nrp1-expressing tissue, suggesting a role in endothelial cell migration towards the inner ear. In summary, Sema signaling may play multiple roles in the developing inner ear.
Asunto(s)
Pollos/metabolismo , Oído Interno/metabolismo , Neuropilina-1/biosíntesis , Semaforinas/biosíntesis , Animales , Movimiento Celular , Embrión de Pollo , Oído Interno/embriología , Regulación del Desarrollo de la Expresión Génica , Mesodermo/metabolismo , Neurogénesis , Neuropilina-1/genética , Órgano Espiral/embriología , Órgano Espiral/metabolismo , Semaforinas/genética , Transducción de Señal , Organismos Libres de Patógenos Específicos , Ganglio Espiral de la Cóclea/embriología , Ganglio Espiral de la Cóclea/metabolismo , Proteínas Wnt/farmacología , Proteínas Wnt/fisiologíaRESUMEN
Semaphorin4A (Sema4A) is a family member of semaphorins expressed in immune cells and is also related with disease progression of tumor disease. In this study, we investigate the expression and pathological role of Sema4A in breast cancer (BCa). Our data showed that the expression of Sema4A increased in the tissues and serum of BCa patients when compared with normal controls. The expression of Sema4A in BCa cells could be induced by hypoxic treatment, whereas silencing hypoxia-inducible factor (HIF)-1α could attenuate the above induced. Furthermore, chromatin immunoprecipitation (ChIP) analysis demonstrated that HIF-1α could regulate the expression of Sema4A through directly binding to the promoter of Sema4A gene, whose enrichment could be further enhanced by hypoxic stimulation. In addition, silencing Sema4A could inhibit the proliferation, vascular endothelial growth factor (VEGF) production and the phosphorylation of Akt, extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) and signal transduction and activator of transcription (STAT)3, but induce apoptosis of BCa cells in the presence of hypoxia. In contrast, recombinant human Sema4A treatment showed the opposite effects. Taken together, these results suggest that Sema4A could promote progression of BCa in the presence of hypoxia and it may hold potential for treatment target for BCa.
Asunto(s)
Neoplasias de la Mama/metabolismo , Progresión de la Enfermedad , Semaforinas/biosíntesis , Hipoxia Tumoral/fisiología , Neoplasias de la Mama/patología , Femenino , Humanos , Células MCF-7 , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Proteínas Recombinantes/farmacología , Semaforinas/genética , Semaforinas/farmacología , Hipoxia Tumoral/efectos de los fármacosRESUMEN
OBJECTIVE: Oral tongue squamous cell carcinoma (OTSCC) is the most frequently encountered malignant epithelial tumors. Semaphorin-7A is a membrane-associated/secreted protein that plays an essential role in the migration and progression of human malignancies. We aimed to investigate the mechanisms of Semaphorin-7A in the growth and migration of OTSCC. MATERIALS AND METHODS: The expressions of Semaphorin-7A in cells were tested by RT-PCR, Western blot, and Immunofluorescence, separately. The activities of OTSCC cells (HSC-3 and Tca8113) were analyzed by MTT, following treatment with Semaphorin-7A or PBS. The migration, invasion, and apoptosis of cells were also determined. The protein expressions of epithelial mesenchymal transition (EMT) pathway were analyzed by Western blot, after treated with Semaphorin-7A in vitro and in vivo. Finally, the mouse model of OTSCC was treated with antibody target for Semaphorin-7A (AntiSema-7A), Semaphorin-7A or PBS, then the tumor size was determined, and histopathological examination and western blot was applied for further confirmation. RESULTS: In OTSCC cells, Semaphorin-7A was highly expressed, and Semaphorin-7A promoted growth in multiple metastatic OTSCC cell lines. Further study indicated that Semaphorin-7A resulted in up-regulation of Snail, N-cadherin and Vimentin expression, and downregulating of E-cadherin. In addition, The Ets2-repressor factor (ERF) expression was down-regulated, and transforming growth factor (TGF-ß)-induced EMT was promoted in OTSCC cells. Then, the proteins of collagen types I (CT-I) and fibronectin (FIB) were also up-regulated after Semaphorin-7A treatment. Furthermore, our results indicated that inhibition of Semaphorin-7A by antibody target for Semaphorin-7A (AntiSema-7A) suppressed OTSCC growth and increased survival in a mouse model of OTSCC. Histopathological examination confirmed the inhibitory effects in vivo. CONCLUSIONS: Semaphorin-7A promoted growth and migration of OTSCC by regulating TGF-ß-induced EMT signaling pathway in OTSCC cells, which provided a new interconnection between the Semaphorin-7A and TGF-ß-induced EMT signaling pathway.
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Antígenos CD/biosíntesis , Movimiento Celular/fisiología , Transición Epitelial-Mesenquimal/fisiología , Semaforinas/biosíntesis , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Neoplasias de la Lengua/metabolismo , Factor de Crecimiento Transformador beta/biosíntesis , Animales , Antígenos CD/genética , Línea Celular Tumoral , Proteínas Ligadas a GPI/biosíntesis , Proteínas Ligadas a GPI/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica/patología , Distribución Aleatoria , Semaforinas/genética , Transducción de Señal/fisiología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Neoplasias de la Lengua/genética , Neoplasias de la Lengua/patología , Factor de Crecimiento Transformador beta/genéticaRESUMEN
Objective: Class 3 semaphorins regulate diverse cellular processes relevant to the pathology of RA, including immune modulation, angiogenesis, apoptosis and invasive cell migration. Therefore, we analysed the potential role of class 3 semaphorins in the pathology of RA. Methods: Protein and mRNA expression in RA synovial tissue, SF and fibroblast-like synoviocytes (FLS) were determined by immunoblotting and quantitative PCR (qPCR). RA FLS migration and invasion were determined using wound closure and transwell invasion assays, respectively. PlexinA1, neuropilin-1 and neuropilin-2 expression was knocked down using small interfering RNA (siRNA). Activation of FLS intracellular signalling pathways was assessed by immunoblotting. Results: mRNA expression of semaphorins (Sema)3B, Sema3C, Sema3F and Sema3G was significantly lower in the synovial tissue of early arthritis patients at baseline who developed persistent disease compared with patients with self-limiting disease after 2 years follow-up. Sema3B and Sema3F expression was significantly lower in arthritis patients fulfilling classification criteria for RA compared with those who did not. FLS expression of Sema3A was induced after stimulation with TNF, IL-1ß or lipopolysaccharides (LPS), while Sema3B and Sema3F expression was downregulated. Exogenously applied Sema3A induced the migration and invasive capacity of FLS, while stimulation with Sema3B or Sema3F reduced spontaneous FLS migration, and platelet-derived growth factor induced cell invasion, effects associated with differential regulation of MMP expression and mediated by the PlexinA1 and neuropilin-1 and -2 receptors. Conclusion: Our data suggest that modulation of class 3 semaphorin signaling could be a novel therapeutic strategy for modulating the invasive behaviour of FLS in RA.
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Artritis Reumatoide/genética , Regulación hacia Abajo , Fibroblastos/metabolismo , Regulación de la Expresión Génica , ARN Mensajero/genética , Semaforinas/genética , Sinoviocitos/metabolismo , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Movimiento Celular , Células Cultivadas , Femenino , Fibroblastos/patología , Humanos , Masculino , Semaforinas/biosíntesis , Membrana Sinovial/metabolismo , Membrana Sinovial/patología , Sinoviocitos/patologíaRESUMEN
Previous meta-analysis has not shown different effects of miR-608 rs4919510 polymorphism in specific cancer types and reported no significant association between rs4919510 and cancer risk among Chinese. However, more recent findings have been inconsistent. Therefore, we performed an updated meta-analysis to examine whether this polymorphism is associated with cancer risk based on ethnicity and type. A total of 18 case-control studies, comprising 12,517 cases and 15,624 controls, were included in our study. Surprisingly, in contrast with previous meta-analysis, a significant association between the rs4919510 polymorphism and cancer risk was observed in Chinese (CG vs CC: odds ratio = 1.11; 95% confidence interval = 1.04-1.19). In further stratified analyses based on cancer type, rs4919510 was significantly associated with an increased risk of papillary thyroid cancer (CG vs CC: odds ratio = 1.25; 95% confidence interval = 1.01-1.54) and exhibited borderline significant associations with increased risk of gastric cancer (GG vs CC: odds ratio = 1.27; 95% confidence interval = 1.00-1.62) and lung cancer (CG vs CC: odds ratio = 1.14; 95% confidence interval = 0.99-1.32), but a decreased risk of colorectal cancer (GG vs CC: odds ratio = 0.74; 95% confidence interval = 0.60-0.91). Moreover, the RegulomeDB database indicated that rs4919510 may affect the expression of two nearby genes ( SEMA4G and MRPL43), and the Cancer Genome Atlas database revealed that the expression level of SEMA4G was significantly lower in colorectal cancer and lung cancer tissues than that in adjacent non-tumour tissues, while the expression level of SEMA4G was significantly higher in gastric cancer tissues than that in adjacent non-tumour tissues. These findings provide evidence that the miR-608 rs4919510 polymorphism may modify cancer susceptibility in a type-specific manner. Furthermore, SEMA4G may function as an oncogene or tumour suppressor to regulate tumour development in a type-specific manner. Further studies with experimental evaluations are warranted.
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Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , MicroARNs/genética , Semaforinas/genética , Pueblo Asiatico , Carcinoma/genética , Carcinoma/patología , Carcinoma Papilar , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Etnicidad , Regulación Neoplásica de la Expresión Génica , Genotipo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Proteínas Mitocondriales/biosíntesis , Proteínas Mitocondriales/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas Ribosómicas/biosíntesis , Proteínas Ribosómicas/genética , Factores de Riesgo , Semaforinas/biosíntesis , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patologíaRESUMEN
Lymph node (LN) metastasis has been suggested as a major prognostic factor for oral cancer. Knockdown of the growth factors and receptors involved in these metastatic mechanisms could significantly reduce LN metastasis and improve the survival of oral cancer patients after treatment. The present study, therefore, aimed to evaluate the expression levels of the following growth factors and receptors in squamous cell carcinoma (SCC) of the tongue: the vascular endothelial growth factor (VEGF)C and VEGFD, which bind to the cell surface tyrosine kinase receptor VEGF receptor3 (VEGFR3); CC motif chemokine receptor 7 (CCR7); neuropilin (NRP)1 and NRP2; and semaphorin 3E (SEMA3E). Furthermore, we assessed microvessel density (MVD) and lymphatic vessel density (LVD) to demonstrate the correlation between these factors and regional LN metastasis, with respect to the clinicopathological features. Finally, we analyzed the correlation between these proteins and overall or diseasefree survival, in order to demonstrate their prognostic value. Univariate analysis revealed a significant association between LN metastasis and the expression levels of VEGFC, VEGFR3, CCR7, NRP1, and SEMA3E, as well as LVD, in SCC cells. In contrast, multivariate analysis identified associations between LN metastasis and NRP1 expression, as well as between LN metastasis and LVD; however, no correlation was found between LN metastasis and the expression levels of the other proteins. The expression levels of VEGFC, VEGFR3, NRP1, and SEMA3E, as well as LVD, were correlated with diseasefree survival time. These results indicate that LN metastasis is associated with poor survival in SCC. This study suggests that NRP1 expression and LVD are independent factors that are likely to predict the risk of LN metastasis in SCC of the tongue, whereas the expression of VEGFC, VEGFR3, CCR7, and SEMA3E are nonindependent predictive factors.
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Carcinoma de Células Escamosas/genética , Neoplasias de la Boca/genética , Neuropilina-1/genética , Receptores CCR7/genética , Semaforinas/genética , Factor C de Crecimiento Endotelial Vascular/genética , Receptor 3 de Factores de Crecimiento Endotelial Vascular/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Vasos Linfáticos/patología , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Neuropilina-1/biosíntesis , Pronóstico , Receptores CCR7/biosíntesis , Semaforinas/biosíntesis , Factor C de Crecimiento Endotelial Vascular/biosíntesis , Receptor 3 de Factores de Crecimiento Endotelial Vascular/biosíntesisRESUMEN
Olfactory sensory axons target well-defined intermediate targets in the zebrafish olfactory bulb called protoglomeruli well before they form odorant receptor-specific glomeruli. A subset of olfactory sensory neurons are labeled by expression of the or111-7:IRES:GAL4 transgene whose axons terminate in the central zone (CZ) protoglomerulus. Previous work has shown that some of these axons misproject to the more dorsal and anterior dorsal zone (DZ) protoglomerulus in the absence of Netrin 1/Dcc signaling. In search of additional cues that guide these axons to the CZ, we found that Semaphorin 3D (Sema3D) is expressed in the anterior bulb and acts as a repellent that pushes them towards the CZ. Further analysis indicates that Sema3D signaling is mediated through Nrp1a, while Nrp2b also promotes CZ targeting but in a Sema3D-independent manner. nrp1a, nrp2b and dcc transcripts are detected in or111-7 transgene-expressing neurons early in development and both Nrp1a and Dcc act cell-autonomously in sensory neurons to promote accurate targeting to the CZ. dcc and nrp1a double mutants have significantly more DZ misprojections than either single mutant, suggesting that the two signaling systems act independently and in parallel to direct a specific subset of sensory axons to their initial protoglomerular target.
Asunto(s)
Neuropilina-1/metabolismo , Neuropilina-2/metabolismo , Bulbo Olfatorio/citología , Vías Olfatorias/embriología , Neuronas Receptoras Olfatorias/citología , Pez Cebra/embriología , Animales , Señales (Psicología) , Receptor DCC , Proteínas de Unión al ADN/metabolismo , Regulación del Desarrollo de la Expresión Génica , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Netrina-1 , Neuropilina-1/genética , Neuropilina-2/genética , Bulbo Olfatorio/crecimiento & desarrollo , Vías Olfatorias/fisiología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/metabolismo , Semaforinas/biosíntesis , Semaforinas/genética , Semaforinas/metabolismo , Transducción de Señal , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
The anterior eye is comprised of an avascular cornea surrounded by a dense periocular vascular network and therefore serves as an excellent model for angiogenesis. Although signaling through PlexinD1 underlies various vascular patterning events during embryonic development, its role during the formation of the periocular vascular network is yet to be determined. Our recent study showed that PlexinD1 mRNA is expressed by periocular angioblasts and blood vessels during ocular vasculogenesis in patterns that suggest its involvement with Sema3 ligands that are concurrently expressed in the anterior eye. In this study, we used in vivo knockdown experiments to determine the role of PlexinD1 during vascular patterning in the anterior eye of the developing avian embryos. Knockdown of PlexinD1 in the anterior eye caused mispatterning of the vascular network in the presumptive iris, which was accompanied by lose of vascular integrity and profuse hemorrhaging in the anterior chamber. We also observed ectopic vascularization of the cornea in PlexinD1 knockdown eyes, which coincided with the formation of the limbal vasculature in controls. Finally we show that Sema3E and Sema3C transcripts are expressed in ocular tissue that is devoid of vasculature. These results indicate that PlexinD1 plays a critical role during vascular patterning in the iris and limbus, and is essential for the establishment of corneal avascularity during development. We conclude that PlexinD1 is involved in vascular response to antiangiogenic Sema3 signaling that guides the formation of the iris and limbal blood vessels by inhibiting VEGF signaling.