RESUMEN
Hepatic stellate cell (HSC) activation is the essential pathological process of liver fibrosis (LF). The molecular mechanisms regulating HSC activation and LF are incompletely understood. Here, we explored the effect of transcription factor SRY-related high mobility group box 7 (SOX7) on HSC activation and LF, and the underlying molecular mechanism. We found the expression levels of SOX7 were decreased in human and mouse fibrotic livers, particularly at the fibrotic foci. SOX7 was also downregulated in primary activated HSCs and TGF-ß1 stimulated LX-2 cells. SOX7 knockdown promoted activation and proliferation of LX-2 cells while inhibiting their apoptosis. On the other hand, overexpression of SOX7 suppressed the activation and proliferation of HSCs. Mechanistically, SOX7 attenuates HSC activation and LF by decreasing the expression of ß-catenin and phosphorylation of Smad2 and Smad3 induced by TGF-ß1. Furthermore, overexpression of SOX7 using AAV8-SOX7 mouse models ameliorated the extent of LF in response to CCl4 treatment in vivo. Collectively, SOX7 suppressed HSC activation and LF. Targeting SOX7, therefore, could be a potential novel strategy to protect against LF.
Asunto(s)
Células Estrelladas Hepáticas , Cirrosis Hepática , Factores de Transcripción SOXF , Células Estrelladas Hepáticas/metabolismo , Animales , Cirrosis Hepática/metabolismo , Cirrosis Hepática/genética , Cirrosis Hepática/patología , Ratones , Humanos , Masculino , Factores de Transcripción SOXF/metabolismo , Factores de Transcripción SOXF/genética , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta1/genética , Proliferación Celular , Ratones Endogámicos C57BL , beta Catenina/metabolismo , beta Catenina/genética , Apoptosis , Proteína Smad2/metabolismo , Proteína Smad2/genética , Línea Celular , Proteína smad3/metabolismo , Proteína smad3/genéticaRESUMEN
Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.
Asunto(s)
Defectos del Tabique Interventricular , Humanos , Aberraciones Cromosómicas , Variaciones en el Número de Copia de ADN/genética , Predisposición Genética a la Enfermedad/genética , Defectos del Tabique Interventricular/genética , Mutación , Factores de Transcripción/genéticaRESUMEN
The lymphatic vasculature plays roles in tissue fluid balance, immune cell trafficking, fatty acid absorption, cancer metastasis, and cardiovascular disease. Lymphatic vessels form by lymphangiogenesis, the sprouting of new lymphatics from pre-existing vessels, in both development and disease contexts. The apical signaling pathway in lymphangiogenesis is the VEGFC/VEGFR3 pathway, yet how signaling controls cellular transcriptional output remains unknown. We used a forward genetic screen in zebrafish to identify the transcription factor mafba as essential for lymphatic vessel development. We found that mafba is required for the migration of lymphatic precursors after their initial sprouting from the posterior cardinal vein. mafba expression is enriched in sprouts emerging from veins, and we show that mafba functions cell-autonomously during lymphatic vessel development. Mechanistically, Vegfc signaling increases mafba expression to control downstream transcription, and this regulatory relationship is dependent on the activity of SoxF transcription factors, which are essential for mafba expression in venous endothelium. Here we identify an indispensable Vegfc-SoxF-Mafba pathway in lymphatic development.
Asunto(s)
Regulación del Desarrollo de la Expresión Génica , Linfangiogénesis/genética , Vasos Linfáticos/embriología , Factor de Transcripción MafB/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Transducción de Señal , Factor C de Crecimiento Endotelial Vascular/metabolismo , Proteínas de Pez Cebra/metabolismo , Animales , Movimiento Celular/genética , Embrión no Mamífero , Factor de Transcripción MafB/genética , Mutación , Proteínas del Tejido Nervioso/genética , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo , Pez Cebra/embriología , Proteínas de Pez Cebra/genéticaRESUMEN
Atrioventricular septal defects (AVSD) are a complicated subtype of congenital heart defects for which the genetic basis is poorly understood. Many studies have demonstrated that the transcription factor SOX7 plays a pivotal role in cardiovascular development. However, whether SOX7 single nucleotide variants are involved in AVSD pathogenesis is unclear. To explore the potential pathogenic role of SOX7 variants, we recruited a total of 100 sporadic non-syndromic AVSD Chinese Han patients and screened SOX7 variants in the patient cohort by targeted sequencing. Functional assays were performed to evaluate pathogenicity of nonsynonymous variants of SOX7. We identified three rare SOX7 variants, c.40C > G, c.542G > A, and c.743C > T, in the patient cohort, all of which were found to be highly conserved in mammals. Compared to the wild type, these SOX7 variants had increased mRNA expression and decreased protein expression. In developing hearts, SOX7 and GATA4 were highly expressed in the region of atrioventricular cushions. Moreover, SOX7 overexpression promoted the expression of GATA4 in human umbilical vein endothelial cells. A chromatin immunoprecipitation assay revealed that SOX7 could directly bind to the GATA4 promoter and luciferase assays demonstrated that SOX7 activated the GATA4 promoter. The SOX7 variants had impaired transcriptional activity relative to wild-type SOX7. Furthermore, the SOX7 variants altered the ability of GATA4 to regulate its target genes. In conclusion, our findings showed that deleterious SOX7 variants potentially contribute to human AVSD by impairing its interaction with GATA4. This study provides novel insights into the etiology of AVSD and contributes new strategies to the prenatal diagnosis of AVSD.
Asunto(s)
Defectos de los Tabiques Cardíacos , Animales , Factor de Transcripción GATA4/genética , Predisposición Genética a la Enfermedad , Defectos de los Tabiques Cardíacos/genética , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Mamíferos , Factores de Transcripción SOXF/genética , Factores de Transcripción SOXF/metabolismo , Factores de Transcripción/genéticaRESUMEN
Diabetic retinopathy (DR) is a high-incidence microvascular complication with retinal neovascularization that generates irreversible visual impairment. However, the mechanism of DR is unclear and needs to be further explored. To explore the the effects of crocetin on expression of NEAT1 and miR-125b-5p and the proliferation activity, migration ability, and angiogenesis ability of human retinal microvascular endothelial cells (hRMECs), RT-qPCR, CCK-8, Transwell, and tube formation assays were performed. Additionally, Western blot was used to detect the expression of SOX7, VEGFA and CD31. Furthermore, a dual-luciferase reporter gene was used to verify the targeting connection. The DR mouse model was constructed by STZ. The effect of crocetin on DR angiogenesis was detected by hematoxylin-eosin (HE) staining, immunohistochemistry (IHC), retinal digest preparations and Western blot. The results showed that crocetin inhibited the high-glucose (Hg)-induced upregulation of NEAT1 and SOX7 and the downregulation of miR-125b-5p. Crocetin inhibited Hg-induced proliferation, migration and angiogenesis by upregulating the targeted inhibition of SOX7 by miR-125b-5p through the inhibition of NEAT1. To summarize, our study revealed that crocetin has a protective effect on Hg-induced DR by regulating the lncRNA NEAT1/miR-125b-5p/SOX7 molecular axis.
Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , MicroARNs , ARN Largo no Codificante , Animales , Carotenoides , Proliferación Celular , Diabetes Mellitus/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/genética , Retinopatía Diabética/metabolismo , Células Endoteliales/metabolismo , Glucosa/metabolismo , Glucosa/toxicidad , Humanos , Ratones , MicroARNs/genética , Neovascularización Patológica/metabolismo , ARN Largo no Codificante/genética , Factores de Transcripción SOXF/metabolismo , Vitamina A/análogos & derivadosRESUMEN
BACKGROUND: Osteosarcoma (OS) is a rare malignant primary tumor of mesenchymal origin affecting bone that occurs in adolescents and children. LncRNAs are important regulators of tumorigenesis and development. This study aimed to explore the role and molecular basis of LncRNA BACE1-AS (BACE1 antisense RNA) in OS. METHODS AND RESULTS: Through the analysis of differential expressed lncRNAs in OS tissues by GEO database, LncRNA BACE1-AS display a remarkably lower expression. This found can also be observed in both OS tissues and cell lines by qRT-PCR. Furthermore, using Cell counting kit-8 (CCK-8), transwell, wound healing and westernblot assays, overexpression LncRNA BACE1-AS remarkably reduce cell proliferation, migration and invasion abilities in OS. In addition, LncRNA BACE1-AS is validated as a sponge of miR-762 through the prediction of lncRNASNP. Further, luciferase reporter and RIP assays are conducted to confirm the binding sites between LncRNA BACE1-AS and miR-762. SRY-box transcription factor 7 (SOX7) target to miR-762 and regulated by LncRNA BACE1-AS. Moreover, inhibition of miR-762 attenuate the role of sh-LncRNA BACE1-AS in OS cells, at meanwhile reduce the expression of SOX7. CONCLUSION: In this study, LncRNA BACE1-AS regulates proliferation, migration and invasion of osteosarcoma cells by miR-762/SOX7 axis, implying that LncRNA BACE1-AS is a potential target for osteosarcoma therapy.
Asunto(s)
Neoplasias Óseas , MicroARNs , Osteosarcoma , ARN Largo no Codificante , Adolescente , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/genética , Neoplasias Óseas/metabolismo , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Niño , Regulación Neoplásica de la Expresión Génica/genética , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Osteosarcoma/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factores de Transcripción SOXF/genética , Factores de Transcripción SOXF/metabolismoRESUMEN
The sex-determining region Y-box 7 (Sox7) is an important member of the SOX F family, which is characterized by a high-mobility-group DNA-binding domain. Previous studies have demonstrated the role of SOX7 in cardiovascular development. SOX7 expression could be detected in normal adult tissues. Furthermore, the expression levels of SOX7 were different in different tumors. Most studies showed the downregulation of SOX7 in tumors, while some studies reported its upregulation in tumors. In this review, we first summarized the upstream regulators (including transcription factors, microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and some exogenous regulators) and downstream molecules (including factors in the Wnt/ß-catenin signaling pathway and some other signaling pathways) of SOX7. Then, the roles of SOX7 in multiple tumors were presented. Finally, the significance of divergent SOX7 expression during cardiovascular development was briefly discussed. The information compiled in this study characterized SOX7 during tumorigenesis and cardiovascular development, which should facilitate the design of future research and promote SOX7 as a therapeutic target.
Asunto(s)
Carcinogénesis , Enfermedades Cardiovasculares/patología , Biología Evolutiva , Neoplasias/patología , Factores de Transcripción SOXF/metabolismo , Animales , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/metabolismo , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Factores de Transcripción SOXF/genética , Transducción de SeñalRESUMEN
During ontogeny, hematopoietic stem and progenitor cells arise from hemogenic endothelium through an endothelial-to-hematopoietic transition that is strictly dependent on the transcription factor RUNX1. Although it is well established that RUNX1 is essential for the onset of hematopoiesis, little is known about the role of RUNX1 dosage specifically in hemogenic endothelium and during the endothelial-to-hematopoietic transition. Here, we used the mouse embryonic stem cell differentiation system to determine if and how RUNX1 dosage affects hemogenic endothelium differentiation. The use of inducible Runx1 expression combined with alterations in the expression of the RUNX1 co-factor CBFß allowed us to evaluate a wide range of RUNX1 levels. We demonstrate that low RUNX1 levels are sufficient and necessary to initiate an effective endothelial-to-hematopoietic transition. Subsequently, RUNX1 is also required to complete the endothelial-to-hematopoietic transition and to generate functional hematopoietic precursors. In contrast, elevated levels of RUNX1 are able to drive an accelerated endothelial-to-hematopoietic transition, but the resulting cells are unable to generate mature hematopoietic cells. Together, our results suggest that RUNX1 dosage plays a pivotal role in hemogenic endothelium maturation and the establishment of the hematopoietic system.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Endotelio Vascular/fisiología , Dosificación de Gen/fisiología , Hemangioblastos/fisiología , Hematopoyesis/genética , Células Madre Hematopoyéticas/fisiología , Animales , Diferenciación Celular/genética , Células Cultivadas , Subunidad alfa 2 del Factor de Unión al Sitio Principal/fisiología , Regulación de la Expresión Génica , Ratones , Ratones NoqueadosRESUMEN
Xenopus primordial germ cells (PGCs) are determined by the presence of maternally derived germ plasm. Germ plasm components both protect PGCs from somatic differentiation and begin a unique gene expression program. Segregation of the germline from the endodermal lineage occurs during gastrulation, and PGCs subsequently initiate zygotic transcription. However, the gene network(s) that operate to both preserve and promote germline differentiation are poorly understood. Here, we utilized RNA-sequencing analysis to comprehensively interrogate PGC and neighboring endoderm cell mRNAs after lineage segregation. We identified 1865 transcripts enriched in PGCs compared with endoderm cells. We next compared the PGC-enriched transcripts with previously identified maternal, vegetally enriched transcripts and found that â¼38% of maternal transcripts were enriched in PGCs, including sox7 PGC-directed sox7 knockdown and overexpression studies revealed an early requirement for sox7 in germ plasm localization, zygotic transcription and PGC number. We identified pou5f3.3 as the most highly expressed and enriched POU5F1 homolog in PGCs. We compared the Xenopus PGC transcriptome with human PGC transcripts and showed that 80% of genes are conserved, underscoring the potential usefulness of Xenopus for understanding human germline specification.
Asunto(s)
Células Germinativas/metabolismo , Factores de Transcripción SOXF/metabolismo , Transcriptoma/fisiología , Proteínas de Xenopus/metabolismo , Cigoto/metabolismo , Animales , Células Germinativas/citología , Humanos , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Transcripción SOXF/genética , Proteínas de Xenopus/genética , Xenopus laevis , Cigoto/citologíaRESUMEN
The endothelial-to-mesenchymal transition (EndMT) is a critical process that occurs during the development of the outflow tract (OFT). Malformations of the OFT can lead to the occurrence of conotruncal defect (CTD). SOX7 duplication has been reported in patients with congenital CTD, but its specific role in OFT development remains poorly understood. To decipher this, histological analysis showed that SRY-related HMG-box 7 (SOX7) was regionally expressed in the endocardial endothelial cells and in the mesenchymal cells of the OFT, where EndMT occurs. Experiments, using in vitro collagen gel culture system, revealed that SOX7 was a negative regulator of EndMT that inhibited endocardial cell (EC) migration and resulted in decreased number of mesenchymal cells. Forced expression of SOX7 in endothelial cells blocked further migration and improved the expression of the adhesion protein vascular endothelial (VE)-cadherin (VE-cadherin). Moreover, a VE-cadherin knockdown could partly reverse the SOX7-mediated repression of cell migration. Luciferase and electrophoretic mobility shift assay (EMSA) demonstrated that SOX7 up-regulated VE-cadherin by directly binding to the gene's promoter in endothelial cells. The coding exons and splicing regions of the SOX7 gene were also scanned in the 536 sporadic CTD patients and in 300 unaffected controls, which revealed four heterozygous SOX7 mutations. Luciferase assays revealed that two SOX7 variants weakened the transactivation of the VE-cadherin promoter. In conclusion, SOX7 inhibited EndMT during OFT development by directly up-regulating the endothelial-specific adhesion molecule VE-cadherin. SOX7 mutations can lead to impaired EndMT by regulating VE-cadherin, which may give rise to the molecular mechanisms associated with SOX7 in CTD pathogenesis.
Asunto(s)
Antígenos CD/metabolismo , Cadherinas/metabolismo , Endocardio/embriología , Cardiopatías Congénitas/embriología , Factores de Transcripción SOXF/metabolismo , Animales , Antígenos CD/genética , Cadherinas/genética , Movimiento Celular , Embrión de Mamíferos , Endocardio/citología , Endotelio/crecimiento & desarrollo , Transición Epitelial-Mesenquimal/fisiología , Femenino , Regulación del Desarrollo de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas , Ratas , Factores de Transcripción SOXF/genéticaRESUMEN
BACKGROUND: Vasculogenic mimicry (VM) is the formation of an alternative circulatory system by aggressive tumor cells. The characteristics of VM and its underlying mechanism in oral squamous cell carcinoma (OSCC) remain unclear. This study aims to determine the relationship between VM in OSCC tissues and clinical outcomes and to investigate the biological role of SOX7 in VM in OSCC cells. METHODS: CD31/PAS staining was performed to evaluate VM in OSCC tissue. The relationships between VM and clinicopathological variables, and VM and SOX7 levels were analyzed. The correlation between SOX7 levels and cancer cohorts was investigated using in silico analysis. VM formation assay was performed to observe VM in vitro. To investigate the role of SOX7 in VM formation, SOX7 was transiently over-expressed in SCC-9 cells. VM-modulating genes were identified by Western blotting. RESULTS: We found a positive correlation between VM and lymph node metastasis and patient survival in OSCC (p = 0.003). In silico analysis from The Cancer Genome Atlas and Gene Expression Omnibus database showed that down-regulation of SOX7 expression was significantly correlated with OSCC patients (p = 0.0187) and lymph node metastasis (p = 0.0017). We also found that the presence of VM in OSCC tissue was inversely associated with SOX7 expression (p = 0.020). We observed that overexpression of SOX7 impaired VM formation by reducing the expression of VE-cadherin, thereby inhibiting cell migration and invasion. CONCLUSION: These results suggest that SOX7 plays an important role in the regulation of VM formation and may inhibit OSCC metastasis.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Humanos , Neovascularización Patológica , Factores de Transcripción SOXF/genética , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. The abnormal expression of long noncoding RNAs (lncRNAs) can facilitate or suppress the development of malignant tumors. lncRNA actin alpha 2, smooth muscle antisense RNA 1 (ACTA2-AS1) has been reported to function as a tumor suppressor in liver cancer, nevertheless, its influences on LUAD remain to be investigated. In this paper, ACTA2-AS1 was identified as a downregulated lncRNA in LUAD samples and cells. Functionally, ACTA2-AS1 overexpression restrained cell proliferation but accelerated cell apoptosis in LUAD. In addition, we determined the suppressive effect of ACTA2-AS1 on LUAD cell invasion, migration, and epithelial-mesenchymal transition progress. Mechanistically, ACTA2-AS1 exert functions as a competing endogenous RNA through serving as a sponge for microRNA-378a-3p (miR-378a-3p) and microRNA-4428 (miR-4428) to elevate SRY-related high-mobility group box 7 (SOX7) expression. Importantly, SOX7 silencing could recover the ACTA2-AS1-mediated cell functions. To summarize, ACTA2-AS1 suppresses the malignant processes of LUAD cells through sequestering miR-378a-3p and miR-4428 to augment SOX7 expression.
Asunto(s)
Adenocarcinoma del Pulmón/metabolismo , ARN Largo no Codificante/genética , Factores de Transcripción SOXF/genética , Células A549 , Actinas/genética , Adenocarcinoma/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Apoptosis/genética , Movimiento Celular/genética , Proliferación Celular/genética , China , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pulmonares/patología , MicroARNs/genética , MicroARNs/metabolismo , ARN sin Sentido/genética , ARN Largo no Codificante/metabolismo , Factores de Transcripción SOXF/metabolismoRESUMEN
BACKGROUND: Antibody-mediated rejection (AMR) can cause graft loss and reduces long-term graft survival after kidney transplantation. Human leukocyte antigen (HLA) and/or non-HLA antibodies play a key role in the pathogenesis of AMR by targeting the allograft epithelium via complement activation and complement-independent mechanisms. However, the precise mechanisms of AMR remain unclear and treatment is still limited. METHODS: In this study, we investigated the role of the endothelial-associated transcription factor Sox7 in AMR, using the anti-HLA antibody W6/32, shRNA-mediated Sox7 knockdown, and by manipulating the Notch pathway. We used an in vitro human kidney glomerular endothelial cells (HKGECs) model and an in vivo MHC-mismatched kidney transplantation model. RESULTS: Sox7 expression was upregulated and the Jagged1-Notch1 pathway was activated in HKGECs after W6/32 activation. W6/32 antibodies increased the expression of adhesion molecules (VCAM-1, ICAM-1), inflammatory cytokines (IL-6, TNF-α), and chemokines (CXCL8, CXCL10), and Sox7 knockdown and inhibition of the Notch pathway by DAPT significantly reduced these effects. Jagged1 overexpression rescued the inhibitory effects of Sox7 knockdown. In addition, Sox7 knockdown attenuated acute allograft kidney injury in mice and reduced the expression of adhesion molecules and Jagged1-Notch1 signaling after transplantation. CONCLUSIONS: Our findings suggest that Sox7 plays an important role in mediating HLA I antibody-dependent endothelial cell activation and acute kidney allograft rejection via the Jagged1-Notch1 pathway. Manipulating Sox7 in donor organs may represent a useful treatment for AMR in solid organ transplantation.
Asunto(s)
Células Endoteliales/inmunología , Rechazo de Injerto/inmunología , Antígenos HLA/inmunología , Trasplante de Riñón/efectos adversos , Factores de Transcripción SOXF/metabolismo , Aloinjertos/inmunología , Animales , Células Cultivadas , Humanos , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores Notch/genética , Receptores Notch/metabolismo , Factores de Transcripción SOXF/genéticaRESUMEN
Clear-cell renal-cell carcinoma (ccRCC) is the most common renal cell carcinoma (RCC), representing 75%-80% of the cases of RCC, and characterized by a high recurrence rate and poor prognosis. miR-452 acts as a tumor promoter in several tumors, including ccRCC. The purpose of this study was to determine the role of miR-452 in ccRCC. miR-452 and SOX7 messenger RNA and protein levels were calculated by quantitative reverse transcription polymerase chain reaction and Western blot analysis. MTT and Transwell assays were utilized to measure proliferative and invasive abilities. The Kaplan-Meier method was used to evaluate the association between the expression of miR-452 or SOX7 and the overall survival of ccRCC patients. Our results showed that miR-452 was overexpressed in ccRCC tissues and cells, and upregulation of miR-452 predicted a poor 5-year survival in ccRCC patients. In contrast, expression of SOX7 was low and downregulation of SOX7 predicted poor prognosis in ccRCC. In addition, miR-452 promoted cell proliferation, invasion, and the EMT, while SOX7 reversed the function of miR-452 on cell proliferation and invasion in 786-O cells. In conclusion, miR-452 was shown to inhibit cell proliferation, invasion, and the EMT through SOX7 in ccRCC, and the newly identified miR-452/SOX7 axis provided novel insight into the pathogenesis of ccRCC.
RESUMEN
Emerging evidence has shown that long noncoding RNA (LncRNA) is involved in the development of epileptogenesis. However, the expression profile and the biological function of FTX in epilepsy remains unclear. This study aimed to provide functional evidence and elucidate the molecular mechanisms by which the FTX affects status epilepticus (SE) induced hippocampal apoptosis. SE rat model was introduced by intraperitoneal injection of lithium chloride and pilocarpine. Our results showed that FTX is notably reduced in the hippocampus. Moreover, the in vivo overexpression of FTX inhibited SE-induced hippocampus neuron apoptosis. Mechanically, we found that FTX negatively regulated miR-21-5p expression by targeting its 3'UTR to regulate neuron apoptosis. Upregulation of miR-21-5p attenuates anti-apoptosis property of FTX overexpression by regulating SOX7 expression in epileptiform hippocampal neurons. Collectively, our study for the first time demonstrated the anti-apoptosis ability of FTX during epileptogenesis and uncovered a novel FTX-mediated mechanism in SE-induced neural apoptosis by targeting miR-21-5p/SOX7 axis, which provides a new target in developing lncRNA-based strategies to reduce SE-induced hippocampal neuron apoptosis.
Asunto(s)
Epilepsia del Lóbulo Temporal/genética , Hipocampo/metabolismo , MicroARNs/genética , ARN Largo no Codificante/genética , Factores de Transcripción SOXF/genética , Animales , Apoptosis/genética , Modelos Animales de Enfermedad , Epilepsia del Lóbulo Temporal/metabolismo , Epilepsia del Lóbulo Temporal/patología , Expresión Génica , Técnicas de Silenciamiento del Gen , Hipocampo/patología , Masculino , MicroARNs/metabolismo , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Sprague-Dawley , Factores de Transcripción SOXF/antagonistas & inhibidores , Factores de Transcripción SOXF/metabolismo , Transducción de Señal , Estado Epiléptico/genética , Estado Epiléptico/metabolismo , Estado Epiléptico/patologíaRESUMEN
Endothelial to hematopoietic transition (EHT) is a dynamic process involving the shutting down of endothelial gene expression and switching on of hematopoietic gene transcription. Although the factors regulating EHT in hemogenic endothelium (HE) of the dorsal aorta have been relatively well studied, the molecular regulation of yolk sac HE remains poorly understood. Here, we show that SOX7 inhibits the expression of RUNX1 target genes in HE, while having no effect on RUNX1 expression itself. We establish that SOX7 directly interacts with RUNX1 and inhibits its transcriptional activity. Through this interaction we demonstrate that SOX7 hinders RUNX1 DNA binding as well as the interaction between RUNX1 and its co-factor CBFß. Finally, we show by single-cell expression profiling and immunofluorescence that SOX7 is broadly expressed across the RUNX1+ yolk sac HE population compared with SOX17. Collectively, these data demonstrate for the first time how direct protein-protein interactions between endothelial and hematopoietic transcription factors regulate contrasting transcriptional programs during HE differentiation and EHT.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/metabolismo , Endotelio/citología , Hemangioblastos/citología , Factores de Transcripción SOXF/metabolismo , Saco Vitelino/citología , Animales , Diferenciación Celular , Células Cultivadas , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteínas de Unión al ADN/antagonistas & inhibidores , Endotelio Vascular/citología , Endotelio Vascular/metabolismo , Femenino , Proteínas HMGB/metabolismo , Células Madre Hematopoyéticas/citología , Masculino , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción SOXF/genética , Transcripción Genética/fisiologíaRESUMEN
Acute myocardial infarction (AMI) induced by ischemia hypoxia severely threatens human life. Cell apoptosis of neurocytes was identified to mediate the pathogenesis, while the potential mechanism was still unclear. Sprague Dawley (SD) rats were used to establish the AMI rat model. Real-time polymerase chain reaction (PCR) and Western blot were performed to detect gene expression in mRNA and protein levels, respectively. A TUNEL assay was carried out to determine cell apoptosis. The relationship between SRY-related HMG-box (SOX7) and miR-128 was verified using luciferase reporter assay. The expression of SOX7 was decreased, while miR-128 was increased in AMI rats and ischemia hypoxia (IH) induced H9c2 cells. Hypoxia induction significantly promoted the expression of interleukin (IL)-33 and soluble ST2 (sST2), and also promoted cell apoptosis. MiR-128 targets SOX7 to regulate its expression. Down-regulated miR-128 reversed the effects of IH on expression of SOX7, sST2 and cell apoptosis, while down-regulated sST2 abolished the effects of miR-128 inhibitor. In addition, overexpressed IL-33 abolished the effects of miR-128 inhibitor that induced by IH on the expression of SOX7 and cell apoptosis. In vivo experiments validated the expression of miR-128 on cell apoptosis. The present study indicated that miR-128 modulated cell apoptosis by targeting SOX7, which was mediated by IL-33/sST2 signaling pathway.
Asunto(s)
Proteína 1 Similar al Receptor de Interleucina-1/metabolismo , Interleucina-33/metabolismo , MicroARNs/metabolismo , Isquemia Miocárdica/metabolismo , Factores de Transcripción SOXF/metabolismo , Enfermedad Aguda , Animales , Apoptosis , Células Cultivadas , Isquemia Miocárdica/patología , Ratas , Ratas Sprague-DawleyRESUMEN
Lung cancer (LC) is one of the leading causes of cancer-related death in the world. miR-24-3p plays critical roles in many cancer types, including LC. In this study, we first investigated whether miR-24-3p promoted LC cell migration and proliferation in vitro. We used three bioinformatics algorithms to predict the miR-24-3p target gene to study the molecular mechanism by which miR-24-3p contributes to LC progression. Then, we used the luciferase reporter assay to identify whether SOX7 was a direct target of miR-24-3p. Moreover, Western blotting and a quantitative real time-polymerase chain reaction analysis showed that miR-24-3p downregulated SOX7 protein expression by a post-transcriptional mechanism. Finally, we determined that SOX7 had opposing effects to those of miR-24-3p on LC cell proliferation and migration, suggesting that miR-24-3p promotes cell proliferation and migration by directly targeting SOX7. Furthermore, miR-24-3p accelerated tumor growth in xenograft mice by targeting SOX7. These results provide the first clue that miR-24-3p could play a role as an oncomiR in LC by regulating SOX7.
Asunto(s)
Movimiento Celular , Proliferación Celular , Neoplasias Pulmonares/metabolismo , MicroARNs/metabolismo , Proteínas de Neoplasias/metabolismo , ARN Neoplásico/metabolismo , Factores de Transcripción SOXF/metabolismo , Células A549 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MicroARNs/genética , Proteínas de Neoplasias/genética , ARN Neoplásico/genética , Factores de Transcripción SOXF/genéticaRESUMEN
SoxF family members have been linked to arterio-venous specification events and human pathological conditions, but in contrast to Sox17 and Sox18, a detailed in vivo analysis of a Sox7 mutant model is still lacking. In this study we generated zebrafish sox7 mutants to understand the role of Sox7 during vascular development. By in vivo imaging of transgenic zebrafish lines we show that sox7 mutants display a short circulatory loop around the heart as a result of aberrant connections between the lateral dorsal aorta (LDA) and either the venous primary head sinus (PHS) or the common cardinal vein (CCV). In situ hybridization and live observations in flt4:mCitrine transgenic embryos revealed increased expression levels of flt4 in arterial endothelial cells at the exact location of the aberrant vascular connections in sox7 mutants. An identical circulatory short loop could also be observed in newly generated mutants for hey2 and efnb2. By genetically modulating levels of sox7, hey2 and efnb2 we demonstrate a genetic interaction of sox7 with hey2 and efnb2. The specific spatially confined effect of loss of Sox7 function can be rescued by overexpressing the Notch intracellular domain (NICD) in arterial cells of sox7 mutants, placing Sox7 upstream of Notch in this aspect of arterial development. Hence, sox7 levels are crucial in arterial specification in conjunction with hey2 and efnb2 function, with mutants in all three genes displaying shunt formation and an arterial block.
Asunto(s)
Animales Modificados Genéticamente/genética , Arterias/embriología , Regulación del Desarrollo de la Expresión Génica/fisiología , Morfogénesis/fisiología , Factores de Transcripción SOXF/genética , Proteínas de Pez Cebra/genética , Pez Cebra/embriología , Angiografía , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Cartilla de ADN/genética , Regulación del Desarrollo de la Expresión Génica/genética , Hibridación in Situ , Morfolinos/genética , Mutación/genética , Flujo Sanguíneo Regional/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción SOXF/metabolismo , Receptor 3 de Factores de Crecimiento Endotelial Vascular/metabolismo , Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
SOX7 is a transcription factor and acts as a tumor suppressor, but its target genes in cancers are poorly explored. We revealed SOX7-mediated gene expression profile in breast cancer cells using microarray chips and discovered multiple altered signaling pathways. When combinatorially analyzing the microarray data with a gene array dataset from 759 breast cancer patients, we identified four genes as potential targets of SOX7 and validated them by quantitative PCR and chromatin immunoprecipitation assays. Among these four genes, we determined that SOX7-activated SPRY1 and SLIT2, and SOX7-repressed TRIB3 and MTHFD2 could all differentially contribute to SOX7-mediated tumor suppression. Overall, we identified multiple cancer-related pathways mediated by SOX7 and for the first time revealed SOX7-regulated target genes in a cancer-relevant context.