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Astrocyte-elevated gene-1 (AEG-1/MTDH/LYRIC) has garnered signficant attention in cancer research, yet, its role in inflammation-associated astrogliosis remains underexplored. This study aims to elucidate the effects of AEG-1 on reactive astrogliosis, including proliferation, migration, and glutamate uptake in primary astrocytes derived from rats. We first confirmed the effect of AEG-1 on these parameters. Subsequently, we investigated whether AEG-1 plays a role in the process of pro-inflammation factors such as tumor necrosis factor-alpha (TNF-α) induced astrogliosis. Our findings revealed that AEG-1-lentivirus infection led to hypertrophic cell bodies and enhanced expression of astrogliosis markers, including glial fibrillary acidic protein (GFAP) and vimentin. Additionally, AEG-1 was found to upregulate the mRNA and protein expression levels of EAAT2, a major glutamate transporter in the brain predominantly expressed by astrocytes and responsible for 90% of glutamate clearance. Furthermore, TNF-α was shown to promote astrogliosis, as well as astrocyte proliferation and migration, by upregulating AEG-1 expression through the NF-κB pathway. Collectively, these results suggest a potential role for AEG-1 in inflammation-related astrogliosis.
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Astrocitos , Gliosis , Proteínas de la Membrana , FN-kappa B , Proteínas de Unión al ARN , Factor de Necrosis Tumoral alfa , Regulación hacia Arriba , Animales , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , FN-kappa B/metabolismo , Gliosis/metabolismo , Gliosis/patología , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Ratas , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ratas Sprague-Dawley , Transducción de Señal , Células Cultivadas , Transportador 2 de Aminoácidos Excitadores/metabolismo , Transportador 2 de Aminoácidos Excitadores/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Ácido Glutámico/metabolismoRESUMEN
In this editorial we provide commentary on the article published by Wang et al, featured in the recent issue of the World Journal of Gastroenterology in 2024. We focus on the metadherin (MTDH), also known as astrocyte elevated gene-1 or lysine rich CEACAM1, and its effects on cancer stem cells (CSCs) and immunity in hepatocellular carcinoma (HCC). HCC is the most common primary liver cancer and one of the leading causes of cancer-related deaths worldwide. Most HCC cases develop in the context of liver cirrhosis. Among the pivotal mechanisms of carcinogenesis are gene mutations, dysregulation of diverse signaling pathways, epigenetic alterations, hepatitis B virus-induced hepatocarcinogenesis, chronic inflammation, impact of tumor microenvironment, oxidative stress. Over the years, extensive research has been conducted on the MTDH role in various tumor pathologies, such as lung, breast, ovarian, gastric, hepatocellular, colorectal, renal carcinoma, neuroblastoma, melanoma, and leukemias. Specifically, its involvement in tumor development processes including transformation, apoptosis evasion, angiogenesis, invasion, and metastasis via multiple signaling pathways. It has been demonstrated that knockdown or knockout of MTDH disrupt tumor development and metastasis. In addition, numerous reports have been carried out regarding the MTDH influence on HCC, demonstrating its role as a predictor of poor prognosis, aggressive tumor phenotypes prone to metastasis and recurrence, and exhibiting significant potential for therapy resistance. Finally, more studies finely investigated the influence of MTDH on CSCs. The CSCs are a small subpopulation of tumor cells that sharing traits with normal stem cells like self-renewal and differentiation abilities, alongside a high plasticity that alters their phenotype. Beyond their presumed role in tumor initiation, they can drive also disease relapse, metastasis, and resistance to chemo and radiotherapy.
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Carcinoma Hepatocelular , Moléculas de Adhesión Celular , Neoplasias Hepáticas , Proteínas de la Membrana , Células Madre Neoplásicas , Humanos , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Moléculas de Adhesión Celular/metabolismo , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Células Madre Neoplásicas/inmunología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Fenotipo , Pronóstico , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Transducción de Señal , Microambiente Tumoral/inmunologíaRESUMEN
Although granule cell dispersion (GCD) in the hippocampus is known to be an important feature associated with epileptic seizures in temporal lobe epilepsy (TLE), the endogenous molecules that regulate GCD are largely unknown. In the present study, we have examined whether there is any change in AEG-1 expression in the hippocampus of a kainic acid (KA)-induced mouse model of TLE. In addition, we have investigated whether the modulation of astrocyte elevated gene-1 (AEG-1) expression in the dentate gyrus (DG) by intracranial injection of adeno-associated virus 1 (AAV1) influences pathological phenotypes such as GCD formation and seizure susceptibility in a KA-treated mouse. We have identified that the protein expression of AEG-1 is upregulated in the DG of a KA-induced mouse model of TLE. We further demonstrated that AEG-1 upregulation by AAV1 delivery in the DG-induced anticonvulsant activities such as the delay of seizure onset and inhibition of spontaneous recurrent seizures (SRS) through GCD suppression in the mouse model of TLE, while the inhibition of AEG-1 expression increased susceptibility to seizures. The present observations suggest that AEG-1 is a potent regulator of GCD formation and seizure development associated with TLE, and the significant induction of AEG-1 in the DG may have therapeutic potential against epilepsy.
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Epilepsia del Lóbulo Temporal , Epilepsia , Animales , Ratones , Astrocitos/metabolismo , Giro Dentado/metabolismo , Epilepsia/metabolismo , Epilepsia del Lóbulo Temporal/inducido químicamente , Epilepsia del Lóbulo Temporal/genética , Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Hipocampo/metabolismo , Ácido Kaínico/efectos adversos , Ácido Kaínico/metabolismo , Convulsiones/inducido químicamente , Convulsiones/genética , Convulsiones/metabolismoRESUMEN
Ovarian cancer (OC) is one of the most common tumors in female reproductive organs with a five-year survival rate of less than 45%. Metastasis is a crucial contributor to OC development. ETS transcription factor (ELK3), as a transcriptional factor, have been involved in multiple tumor development. However, its role in OC remains elusive. In this study, we observed high expression of ELK3 and AEG1 in human OC tissues. OVCAR-3 and SKOV3 cells were treated with hypoxia to mimic tumor microenvironment in vivo. We found that the expression of ELK3 was significantly increased in cells under hypoxia compared with normoxia. ELK3 knockdown inhibited cell migration and invasion abilities under hypoxia. Moreover, ELK3 knockdown decreased ß-catenin expression and inhibited the activation of Wnt/ß-catenin pathway in SKOV3 cells under hypoxia. Astrocyte-elevated gene-1 (AEG1) has been reported to promote OC progression. Our results showed that the mRNA level of AEG1 was decreased when ELK3 knockdown under hypoxia. Dural luciferase assay confirmed that ELK3 bound to gene AEG1 promoter (-2005-+15) and enhanced its transcriptional activity under hypoxia. Overexpression of AEG1 increased the migration and invasion abilities of SKOV3 cell with ELK3 knockdown. In the absence of ELK3, the activation of ß-catenin was recovered by AEG1 overexpression. To sum up, we conclude that ELK3 promotes AEG1 expression by binding to its promoter. ELK3 could promote migration and invasion of OC cells by targeting AEG1, which provides a potential basis for therapeutic approaches to OC.
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MicroARNs , Neoplasias Ováricas , Femenino , Humanos , Apoptosis , Astrocitos/patología , beta Catenina/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Hipoxia , MicroARNs/genética , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Microambiente TumoralRESUMEN
Hepatocellular carcinoma (HCC) remains the third leading malignancy worldwide, causing high mortality in adults and children. The neuropathology-associated gene AEG-1 functions as a scaffold protein to correctly assemble the RNA-induced silencing complex (RISC) and optimize or increase its activity. The overexpression of oncogenic miRNAs periodically degrades the target tumor suppressor genes. Oncogenic miR-221 plays a seminal role in the carcinogenesis of HCC. Hence, the exact molecular and biological functions of the oncogene clusters miR-221/AEG-1 axis have not yet been examined widely in HCC. Here, we explored the expression of both miR-221 and AEG-1 and their target/associate genes by qRT-PCR and western blot. In addition, the role of the miR-221/AEG-1 axis was studied in the HCC by flow cytometry analysis. The expression level of the AEG-1 did not change in the miR-221 mimic, and miR-221-transfected HCC cells, on the other hand, decreased the miR-221 expression in AEG-1 siRNA-transfected HCC cells. The miR-221/AEG-1 axis silencing induces apoptosis and G2/M phase arrest and inhibits cellular proliferation and angiogenesis by upregulating p57, p53, RB, and PTEN and downregulating LSF, LC3A, Bcl-2, OPN, MMP9, PI3K, and Akt in HCC cells.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroARNs , Carcinoma Hepatocelular/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Niño , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Hepáticas/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Interferente Pequeño , Complejo Silenciador Inducido por ARN/genética , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Astrocyte elevated gene-1 (AEG-1) is a key regulatory factor of progression in multiple types of tumor and neurodegenerative disease development. AEG-1 is associated with glutamate excitotoxicity due to its reported function of repressing excitatory amino acid transporter 2 expression in astrocytes. Although the function of AEG-1 has been demonstrated in neurological disorders, such as Alzheimer's disease and amyotrophic lateral sclerosis, the underlying mechanism of neuronal AEG-1 function remains unclear. The aim of the present study was to clarify the function and related mechanism of AEG-1 in neurons. A stable AEG-1-deficient HT22 neuronal cell line was constructed using CRISPR/Cas9 gene-editing technology. Reverse transcription-quantitative PCR and western blotting were carried out to analyze the knockdown efficiency of AEG-1-deficient HT22 cell line. RNA Sanger sequencing analysis was performed in AEG-1-deficient HT22 cells and wild-type HT22 cells without knockout (KO). Results from RNA sequencing revealed that AEG-1 modulated neuronal morphology and development by regulating the expression of numerous genes, such as ubiquitin C, C-X-C motif chemokine ligand 1, MMP9, Notch1, neuropilin 1 and ephrin type-A receptor 4. In addition, AEG-1 deficiency impacted several signaling pathways by mediating cell survival differentiation, apoptosis, and migration; this included the TNF-α pathway, the NF-κB pathway, the MAPK signaling pathway, the Notch signaling pathway and Axon guidance. Downregulation in cellular ion homeostasis, including ion channel function and neurotransmitter release, were observed after knocking out AEG-1 expression. Collectively, the present study provides insights into AEG-1-dependent gene regulation and signaling pathway transduction in neurons. The results of the present study may be applied for improving the understanding of AEG-1-associated central nervous system diseases.
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OBJECTIVE: This study aimed to investigate the effects of downregulating astrocyte elevated gene-1 (AEG-1) expression combined with all-trans retinoic acid (ATRA) on vasculogenic mimicry (VM) formation and angiogenesis in glioma. METHODS: U87 glioma cells were transfected with AEG-1 shRNA lentiviral vectors (U87-siAEG-1) and incubated in a medium containing 20 µmol/L ATRA. Matrigel-based tube formation assay was performed to evaluate VM formation, and the cell counting kit-8 (CCK-8) assay was used to analyze the proliferation of glioma cells in vitro. Reverse transcription-quantitative polymerase chain reaction and Western blot analysis were used to investigate the mRNA and protein expression of related genes, respectively. Glioma xenograft models were generated via subcutaneous implantation of glioma cells in nude mice. Tumor-bearing mice received an intraperitoneal injection of ATRA (10 mg/kg per day). Immunohistochemistry was used to evaluate the expression of related genes and the microvessel density (MVD) in glioma xenograft models. CD34/periodic acid-Schiff double staining was performed to detect VM channels in vivo. The volume and weight of tumors were measured, and a tumor growth curve was drawn to evaluate tumor growth. RESULTS: A combination of ATRA intervention and downregulation of AEG-1 expression significantly inhibited the proliferation of glioma cells in vitro and glioma VM formation in vitro and in vivo. It also significantly decreased MVD and inhibited tumor growth. Further, the expression levels of matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial-cadherin (VE-cadherin), and vascular endothelial growth factor (VEGF) in glioma significantly decreased in vivo and in vivo. CONCLUSION: Hence, a combinatorial approach might be effective in treating glioma through regulating MMP-2, MMP-9, VEGF, and VE-cadherin expression.
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Glioma , Metaloproteinasa 9 de la Matriz , Animales , Astrocitos/patología , Línea Celular Tumoral , Regulación hacia Abajo , Glioma/tratamiento farmacológico , Glioma/genética , Humanos , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/genética , Tretinoina/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
It is unclear which prognostic factor such as pathological features and gene mutation are majorly relevant for stage III disease and whether they aid in determining patients who will be benefit from postoperative adjuvant chemotherapy. The expression of astrocyte-elevated gene-1 (AEG-1), thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF) was examined to investigate their role in adjuvant chemotherapy for patients with resectable stage III colorectal cancer (CRC). A significant positive correlation was observed between AEG-1, TS, ERCC1, EGFR, and VEGF gene expression levels in CRC cell lines, and low AEG-1 and TS expression were highly sensitive to 5-fluorouracil treatment. Our results showed that AEG-1 expression was high in T4 and caused CRC recurrence or metastasis. Patients with T4, high AEG-1, TS and VEGF expression had a significantly short disease-free survival and overall survival. In multivariate Cox regression analysis, high AEG-1 expression could be an independent prognostic factor indicating poor survival in patients with resectable stage III CRC treated with adjuvant chemotherapy. In conclusion, AEG-1 expression and tumor grade are potential prognostic factors for recurrence and survival in patients with stage III CRC receiving adjuvant fluoropyrimidine-based chemotherapy.
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Adenocarcinoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Proteínas de la Membrana/metabolismo , Proteínas de Unión al ARN/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Quimioterapia Adyuvante , Colectomía , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios RetrospectivosRESUMEN
An array of human cancers, including hepatocellular carcinoma (HCC), overexpress the oncogene Astrocyte elevated gene-1 (AEG-1). It is now firmly established that AEG-1 is a key driver of carcinogenesis, and enhanced expression of AEG-1 is a marker of poor prognosis in cancer patients. In-depth studies have revealed that AEG-1 positively regulates different hallmarks of HCC progression including growth and proliferation, angiogenesis, invasion, migration, metastasis and resistance to therapeutic intervention. By interacting with a plethora of proteins as well as mRNAs, AEG-1 regulates gene expression at transcriptional, post-transcriptional, and translational levels, and modulates numerous pro-tumorigenic and tumor-suppressive signal transduction pathways. Even though extensive research over the last two decades using various in vitro and in vivo models has established the pivotal role of AEG-1 in HCC, effective targeting of AEG-1 as a therapeutic intervention for HCC is yet to be achieved in the clinic. Targeted delivery of AEG-1 small interfering ribonucleic acid (siRNA) has demonstrated desired therapeutic effects in mouse models of HCC. Peptidomimetic inhibitors based on protein-protein interaction studies has also been developed recently. Continuous unraveling of novel mechanisms in the regulation of HCC by AEG-1 will generate valuable knowledge facilitating development of specific AEG-1 inhibitory strategies. The present review describes the current status of AEG-1 in HCC gleaned from patient-focused and bench-top studies as well as transgenic and knockout mouse models. We also address the challenges that need to be overcome and discuss future perspectives on this exciting molecule to transform it from bench to bedside.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Astrocitos/metabolismo , Carcinoma Hepatocelular/genética , Humanos , Neoplasias Hepáticas/genética , Proteínas de la Membrana/metabolismo , Ratones , Proteínas de Unión al ARNRESUMEN
[This corrects the article DOI: 10.3389/fonc.2019.00847.].
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Multifunctional in nature, the protein Astrocyte Elevated Gene-1 (AEG-1) controls several cancers through protein-protein interactions. Although, specific physiological processes and molecular functions linked with AEG-1 interactors remain unclear. In our present study, we procured the data of AEG-1 interacting proteins and evaluated their biological functions, associated pathways, and interaction networks using bioinformatic tools. A total of 112 proteins experimentally detected to interact with AEG-1 were collected from various public databases. DAVID 6.8 Online tool was utilized to identify the molecular functions, biological processes, cellular components that aid in understanding the physiological function of AEG-1 and its interactors in several cell types. With the help of integrated network analysis of AEG-1 interactors using Cytoscape 3.8.0 software, cross-talk between various proteins, and associated pathways were revealed. Additionally, the Enrichr online tool was used for performing enrichment of transcription factors of AEG-1 interactors' which further revealed a closely associated self-regulated interaction network of a variety of transcription factors that shape the expression of AEG-1 interacting proteins. As a whole, the study calls for better understanding and elucidation of the pathways and biological roles of both AEG-1 and its interactor proteins that might enable their application as biomarkers and therapeutic targets in various diseases in the very near future.
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Proteínas de la Membrana/química , Proteínas de Unión al ARN/química , Programas Informáticos , Factores de Transcripción/química , Humanos , Proteínas de la Membrana/aislamiento & purificación , Proteínas de la Membrana/metabolismo , Unión Proteica , Proteínas de Unión al ARN/aislamiento & purificación , Proteínas de Unión al ARN/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Chemotherapeutic resistance represents a major obstacle for the treatment of patients with non-small cell lung cancer (NSCLC); however, the associated molecular mechanisms underpinning the development of resistance remain poorly characterized. In the current study, 5-fluorouracil (5-FU)-resistant A549 cells (A549/5-FU) were generated from A549 cells. Reverse transcription-quantitative PCR and western blotting were used to detect microRNA(miR)-124-5p and astrocyte elevated gene 1 (AEG-1) expression levels in cells and tumor tissues. In addition, the cytotoxic effect of 5-FU on the cells was determined using the Cell Counting Kit-8 assay, and the Dual-luciferase reporter assay was used to validate AEG-1 as a target gene of miR-124-5p. Transfection with a miR-124-5p mimic enhanced inhibition of cell viability induced by 5-FU in A549/5-FU cells, whereas miR-124-5p inhibitor transfection partially reversed 5-FU-induced cell viability inhibition in A549 and H1299 cells. A decrease in miR-124-5p expression level was observed in A549/5-FU cells compared with the parental A549 cells. Furthermore, AEG-1 was predicted as a target gene of miR-124-5p, and its expression was increased in A549/5-FU cells compared with A549 cells. Additionally, the upregulation of miR-124-5p was associated with lower expression levels of AEG-1 in A549/5-FU cells, compared with parental A549 cells. Moreover, the Dual-luciferase reporter assay confirmed the ability of miR-124-5p to bind directly to the 3'-untranslated region of AEG-1 mRNA. Notably, the overexpression of AEG-1 reversed the ability of the miR-124-5p mimic to increase the sensitivity of A549/5-FU cells to 5-FU treatment. Additionally, a significant negative correlation between miR-124-5p expression and AEG-1 mRNA levels was detected in 40 pairs of NSCLC tissues and their corresponding adjacent paracancerous tissues. The results of the present study indicated that miR-124-5p may regulate the chemotherapeutic sensitivity of NSCLC cells, and may therefore represent a promising biomarker or therapeutic target for patients with NSCLC.
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Vasculogenic mimicry (VM) contributes to the resistance of anti-angiogenic therapies in glioma. Certain genes, including MMP-2 and VEGF may be associated with the development of VM. Astrocyte elevated gene-1 (AEG-1) is considered to be an oncogene that promotes autophagy, invasion, metastasis, angiogenesis and drug resistance; however, the association between AEG-1 and VM formation is still unknown. The present study investigated the effects of AEG-1 downregulation on VM formation in the U87 glioma cell line in vitro and in xenograft models of glioma, and the potential underlying mechanisms of action. In the present study, U87 glioma cells were infected with the AEG-1 short hairpin RNA lentivirus. A Matrigel-based tube formation assay was performed to evaluate VM formation in vitro. Reverse transcription-quantitative PCR and western blot analysis were conducted to investigate the mRNA and protein expression levels of MMP-2 and VEGF. Glioma xenograft models were generated through the intracerebral implantation of U87 glioma cells into nude rats; CD34/Periodic Acid-Schiff double-staining was performed to detect VM channels in vivo. Following AEG-1 downregulation in U87 cells, the development of VM was significantly decreased in vitro and in vivo. In addition, the expression levels of MMP-2 and VEGF in glioma cells were decreased compared with the control group. These results suggested that downregulation of AEG-1 expression could significantly inhibit the development of VM in gliomas, both in vitro and in vivo, and may be partially related to the regulation of VEGF and MMP-2 expression.
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Astrocyte elevated gene-1 (AEG-1) is an oncogene and a critical signaling molecule that has a wide variety of interactions with other oncogenes and tumor suppressor genes, leading to increasing malignant properties of malignant gliomas, such as invasion, angiogenesis, metastasis, and chemoresistance. Its overexpression is enhanced by many factors such as exposure of the cells to human immunodeficiency virus type 1 (HIV-1), HIV-1 envelop glycoprotein 120, hypoxia, or glucose deprivation. Thorough understanding of these interactions along with AEG-1 inducers and repressors is important in setting a successful treatment plan targeting this oncogene. Since its discovery in 2002, AEG-1 has made a significant impact in improving our understanding of mechanism of malignant tumors progression, such as breast carcinomas, melanoma, and malignant gliomas. Therefore, it has been a novel therapeutic target for the past two decades. Herein, we focus on the role of AEG-1 in malignant gliomas and its interaction with other signaling molecules.
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Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Proteínas de la Membrana/genética , Oncogenes , Proteínas de Unión al ARN/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioma/genética , Glioma/patología , HumanosRESUMEN
The aim of this study is to investigate the role of microRNA-499 (miR-499) in hepatocellular carcinoma tumor growth and the underlying molecular mechanisms. The expression of miR-499 was significantly decreased in hepatocellular carcinoma tissues compared with that in adjacent normal tissues. Furthermore, miR-499 overexpression in HEPG2 cell was related to the tumor growth in nude mice xenograft models. Likewise, miR-499 mimic or inhibitor decreased or accelerated cell proliferation, respectively. Mechanistically, miR-499 directly targeted the 3'- untranslated region of astrocyte elevated gene-1 and downregulate astrocyte elevated gene-1 expression. Restoration of astrocyte elevated gene-1 expression in hepatocellular carcinoma cells reversed the inhibitory effect of miR-499 on cell growth. In addition, astrocyte elevated gene-1 and miR-499 expression were inversely correlated in human and mice hepatocellular carcinoma tissues. Our study identified miR-499 as a tumor-suppressive miR in hepatocellular carcinoma, thus providing a candidate therapeutic target for the future diagnosis or treatment of hepatocellular carcinoma.
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Carcinoma Hepatocelular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas/genética , Proteínas de la Membrana/genética , MicroARNs/genética , Interferencia de ARN , Proteínas de Unión al ARN/genética , Regiones no Traducidas 3' , Animales , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Células Hep G2 , Xenoinjertos , Humanos , Ratones , Carga TumoralRESUMEN
PURPOSE: The long noncoding RNA DLGAP1 antisense RNA 1 (DLGAP1-AS1) plays well-defined roles in the malignant progression of hepatocellular carcinoma. The purpose of this study was to determine whether DLGAP1-AS1 affects the aggressive behavior of gastric cancer (GC). METHODS: DLGAP1-AS1 expression in GC tissue samples and cell lines was determined by reverse-transcription quantitative PCR. GC cell proliferation, apoptosis, migration, invasion, and tumor growth in vitro as well as in vivo were examined by the Cell Counting Kit-8 assay, flow-cytometric analysis, transwell migration and invasion assays, and xenograft model experiments, respectively. RESULTS: DLGAP1-AS1 was overexpressed in GC tissue samples and cell lines. Among patients with GC, the increased level of DLGAP1-AS1 correlated with tumor size, TNM stage, lymph node metastasis, distant metastasis, and shorter overall survival. The knockdown of DLGAP1-AS1 suppressed GC cell proliferation, migration, and invasion in vitro, as well as promoted cell apoptosis and hindered tumor growth in vivo. Mechanistically, DLGAP1-AS1 functioned as a competing endogenous RNA for microRNA-628-5p (miR-628-5p) in GC cells, thereby increasing the expression of the miR-628-5p target astrocyte elevated gene 1 (AEG-1). Functionally, the recovery of the miR-628-5p/AEG-1 axis output attenuated the effects of DLGAP1-AS1 knockdown in GC cells. CONCLUSION: DLGAP1-AS1 is a pleiotropic oncogenic lncRNA in GC. DLGAP1-AS1 plays a pivotal part in the oncogenicity of GC in vitro and in vivo by regulating the miR-628-5p/AEG-1 axis. DLGAP1-AS1, miR-628-5p, and AEG-1 form a regulatory pathway to facilitate GC progression, suggesting this pathway as an effective target for the treatment of GC.
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BACKGROUND: The study explored the potential function of astrocyte elevated gene-1 (AEG-1) on angiogenesis in tongue squamous cell carcinoma (TSCC) in TSCC cell lines. METHODS: The different degrees of angiogenesis were detected in TSCC cell lines expressing different levels of AEG-1 by chick chorioallantoic membrane (CAM) experimental model. Next, we established xenografts of different TSCC cell lines with different expression levels of AEG-1 in nude mice and conducted immunohistochemistry to evaluate the expression of the angiogenesis-associated factor, that is, vascular endothelial growth receptor factor 2 (VEGFR-2) and microvessel density (MVD). Vascular endothelial growth factor (VEGF) was detected by ELISA. RESULTS: CAM assay showed that the number of vessels was significantly reduced in AEG-1-down um1 cell line (p < .05), whereas the number was significantly increased in AEG-1-over um2 cell line (p < .05). Moreover, up-regulated AEG-1 expression level was associated with higher tumor angiogenesis, which was reflected by augmented expression levels of VEGF (p < .01), VEGFR-2 (p < .05), and MVD counting (p < .01). CONCLUSIONS: This study demonstrated that AEG-1 can promote tumor angiogenesis in TSCC and inhibition of tumor angiogenesis by repressing the expression of AEG-1 may be a novel potential treatment approach for TSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Proteínas de la Membrana , Proteínas de Unión al ARN , Neoplasias de la Lengua , Animales , Astrocitos , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/genética , Moléculas de Adhesión Celular/genética , Línea Celular Tumoral , Xenoinjertos , Humanos , Proteínas de la Membrana/fisiología , Ratones , Ratones Desnudos , Pronóstico , Proteínas de Unión al ARN/fisiología , Neoplasias de la Lengua/tratamiento farmacológico , Neoplasias de la Lengua/genética , Factor A de Crecimiento Endotelial VascularRESUMEN
Astrocyte elevated gene-1 (AEG-1) plays a critical role in the development, progression, and metastasis of a variety of cancers, including non-small-cell lung cancer (NSCLC). The objective of the current study is to unravel the upstream signaling of AEG-1. A cohort of 28 NSCLC tissues and 30 normal tissues were collected. Quantitative reverse transcription-polymerase chain reaction and Western blotting were used to examine AEG-1, migration, and invasion related markers in NSCLC cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay coupled with colony formation assay were conducted to monitor cell growth. Transwell assay was performed to determine cell migration and invasion. Apoptotic cells were detected by costaining with Annexin-V-fluorescein isothiocyanate and propidium iodide. Immunofluorescent staining was used to observe the levels of migration and invasion related markers. Xenograft models were used to investigate tumor formation in vivo. Dual-luciferase reporter assay and RNA immunoprecipitation were carried out to determine the interaction between circMTDH.4 and miR-630, as well as the associated between miR-630 and AEG-1. AEG-1 was highly expressed in NSCLC tissues and cell lines. Silencing of AEG-1 inhibited cell proliferation, migration, invasion, and chemoresistance/radioresistance in NCI-H1650 and A549 cells. circMTDH.4 regulated AEG-1 expression via sponging miR-630. Knockdown of circMTDH.4 and/or overexpression of miR-630 inhibited chemoresistance and radioresistance in NSCLC cells, whereas overexpression of AEG-1 or knockdown of miR-630 exerted rescue effects. circMTDH.4/miR-630/AEG-1 axis is responsible for chemoresistance and radioresistance in NSCLC cells.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Proteínas de la Membrana/genética , MicroARNs/genética , ARN Circular/genética , Proteínas de Unión al ARN/genética , Células A549 , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/terapia , Línea Celular Tumoral , Quimioradioterapia , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Interferencia de ARN , Tolerancia a Radiación/genética , Trasplante HeterólogoRESUMEN
MicroRNA-520e (miR-520e) is increasingly being recognized as a cancer-related miRNA in multiple cancer types; however, little is known about its role in colorectal cancer. In this study, we determined the specific role of miR-520e in colorectal cancer. Expression of miR-520e was lower in colorectal cancer tissues compared to normal tissues. Overexpression of miR-520e significantly decreased the proliferation, colony formation and invasion of colorectal cancer cells, while inhibition of miR-520e exhibited the opposite effect. Moreover, miR-520e was found to target the 3'-untranslated region of astrocyte elevated gene-1 (AEG-1) and inhibit AEG-1 expression in colorectal cancer cells. An inverse correlation between miR-520e and AEG-1 expression was confirmed in colorectal cancer tissues. Notably, miR-520e suppressed the phosphorylation of glycogen synthase kinase-3ß and decreased the expression of ß-catenin, leading to inactivation of Wnt/ß-catenin signalling in colorectal cells. A rescue assay confirmed that miR-520e regulates cell proliferation, invasion and Wnt/ß-catenin signalling through targeting AEG-1. Taken together, these results indicate that miR-520e plays a critical role in regulating colorectal cancer cell proliferation and invasion by inhibiting Wnt/ß-catenin signalling via AEG-1. Our study highlights the importance of the miR-520e/AEG-1/Wnt/ß-catenin signalling axis in colorectal cancer, thus targeting miR-520e may represent an effective therapeutic strategy.
Asunto(s)
Proliferación Celular/genética , Neoplasias Colorrectales/genética , Glucógeno Sintasa Quinasa 3 beta/genética , Proteínas de la Membrana/genética , MicroARNs/genética , Proteínas de Unión al ARN/genética , Vía de Señalización Wnt/genética , beta Catenina/genética , Regiones no Traducidas 3'/genética , Astrocitos/patología , Células CACO-2 , Línea Celular , Línea Celular Tumoral , Movimiento Celular/genética , Neoplasias Colorrectales/patología , Regulación Neoplásica de la Expresión Génica/genética , Células HCT116 , Células HEK293 , HumanosRESUMEN
BACKGROUND: To explore the expression and correlation of B-cell-specific Moloney murine leukemia virus insertion site 1 (Bmi-1), astrocyte elevated gene-1 (AEG-1) and fragile histidine triad (FHIT) in bladder transitional cell carcinoma (BTCC). METHODS: Forty-six tissue samples were obtained from patients diagnosed with primary bladder cancer during the first radical cystectomy between June 2010 and January 2014. The expression of Bmi-1, AEG-1 and FHIT in normal tissues and BTCC tissues in different histological cell types, clinical pathological stages and lymph node metastatic status were evaluated by quantitative real time polymerase chain reaction (qRT-PCR), Western blot and immunohistochemistry. Relationships between Bmi-1, AEG-1 and FHIT were determined using linear correlation coefficient. RESULTS: The results of qRT-PCR showed the relative expression of Bmi-1 and AEG-1 were higher and the expression of FHIT was lower in BTCC tissues than those in normal tissues, whether in different histological cell types, clinical pathological stages or lymph node metastatic status (P<0.05). Similarly, the up-regulated expression of Bmi-1 and AEG-1 and down-regulated expression of FHIT in BTCC tissues were observed by the Western blot and immunohistochemistry compared with normal tissues (P<0.05). Linear correlation analysis showed the expression of Bmi-1 was positively correlated with AEG-1 (r>0.90, P<0.01), which was negatively correlated with the expression of FHIT, respectively (r=-0.84, P<0.05). CONCLUSIONS: The study demonstrated the up-regulated expression of Bmi-1 and AEG-1 and the down-regulated expression of FHIT in BTCC tissues. The interaction of Bmi-1, AEG-1 and FHIT may involve in the tumorigenesis, progression and invasion of BTCC through NF-κB/MMP-9 pathway.